About

Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Saturday, October 30, 2010

Suboxone and Subutex: Still nothing... on a generic for the first

Since the expiration of the patent for the Suboxone Sublingual Tablet, Reckitt Benckiser has worked hard to prevent the availability of generic formulations which would lead to reductions in price.

In 2009, Suboxone was selling for an average of 7.00$ per TABLET in most areas of the US. It is now 2011, and my particular pharmacy has just increased the price from 7 to 8 dollars per tablet. Suboxone film is the same price.

There are multiple generics for the buprenorphne only product, Subutex - which are available at an ever more competitive price; about 2.50$ per 8mg tablet as of 2010. 

Update: 10/27/2011

For years we have hoped and waited for the availability of a generic for Suboxone, to no avail.
Unfortunately in 2010, RB introduced a new version of Suboxone which they claim to be "Superior" to the original; this is a common technique used by Drug Companies, to release a modified version of their product once the original patent has expired; in hopes of keeping a large market share of sales for the drug. Additionally however, the comany has convinced insurance companies to restrict their coverage to the FILM formulation - For should any generic TABLET arrive, many insurers will not be covering it.

RB has aggressively promoted the film to Physicians and Pharmacists, claiming the "old" tablet version to be unsafe, unstable, and obsolete. Once a generic buprenorphine/naloxone tablet does come to market, I'm sure Reckitt Benckiser will have stopped producing their own suboxone tablet and convinced insurance carriers only to cover the film (they've reportedly already began doing the latter), yet again assuring themselves a market monopoly by ensuring that their film is dispensed to a much greater scale than any generic tablet formulation.

Additionally since the release of the film, RB has been warning clinicians and insurance carriers of the supposedly greater abuse potential and danger of buprenorphine only products, which they are claiming should be used for short term detox purposes only, rather than long term maintenance - Never mind the fact that the naloxone present in suboxone does little to prevent improper administraton, and that the buprenorphine only product is virtually no more of an abuse liability than Suboxone in "non-addict" or recreational users. Unfortunately this basic pharmacological concept eludes even some physicians, who are often reluctant to prescribe Subutex.

As of yet, no one knows.. well... anything.. And as long as Reckitt fucking Benckiser continues manipulating and monopolizing the market, it just might remain this way for the next several years... I would boycott these sick fucks if it were in any way practical...

Fentanyl & Analogues

Fentanyl


Basic:

Fentanyl is a potent and fast acting synthetic opioid. First synthesized in Europe by Dr. Paul Jannsen (Jannsen Pharmaceutica) who discovered its properties while doing binding assays of pethidine analogues.

Use:

In the US, fentanyl is used as a first or second line agent for a variety of indications including; emergency room, critical care, or post operative analgesia, a component of anaesthetic induction & maintenance of general anaesthesia, perioperative analgesia during 'conscious' procedures using regional anaesthesia, for procedural sedation often combined with a benzodiazapine prior to endotracheal intubation, etc, spinal analgesia, end of life palliative care (hospice), and in more recent years as a prescription non-parenteral analgesic for outpatient treatment of moderate to severe pain. Non parenteral fentanyl is delivered in doses of 100 to 1600 micrograms (instant release), or 12 to 100 micrograms per hour (sustained release). Parenteral fentanyl in the clinic or hospital setting is delivered in doses commonly ranging 25 to 150 micrograms as a single injection every few hours. In an surgical anaesthesia or critical care setting with the use of assisted ventilation, fentanyl is delivered in weight based doses as high as 50 to 150 micrograms per kilogram, depending on the degree of antinociception desired for the particular procedure. This is possible due to the use of assisted ventilation and extensive monitoring by the anaesthetist and team.

Fentanyl is typically the first choice among hospitalists for procedural sedation; i.e. setting broken bones, inserting catheters, obtaining CSF samples via lumbar puncture, or endotracheal intubation. The drgu can be be administered shortly before such a procedure along with midazolam or propofol - fentanyl provides analgesia while the sadative/hypnotic provides retrograde amnesia (the inability to remember the incident or discomfort). A trait which lends to its appeal in perioperative analgesia (anaesthesia) is its rapid onset & short duration; this allows a wider margin of safety in IV infusions during surgery, due to the continuous rate of elimination which takes place with the ongoing administration (the simplest way to describe this would be a revolving door effect) Furthermore, the short duration allows faster anaesthesia recovery time in the case of outpatient surgery, which in a busy facility promotes higher rates of patient turnover.

fentanyl transdermal patches
(used in treating chronic pain)
Fentanyl within the last 20 years has evolved as an effective opioid for outpatient use. The Duragesic transdermal patch was introduced to the US in the mid 90's - Duragesic is the original brand name for the transdermal fentanyl skin-patch, which when applied dermally delivers a set-hourly dose of the drug absorbed through the flesh. The patch lasts up to 72 hours, and comes in hourly dosages of 12ug/h, 25ug/h, 50ug/h, 75ug/h, 100ug/h. The patches exist in Europe as "Durogesic" - the US product is manufactured by ALZA corporation and marketed by Jannsen Pharmaceutica, both are subsidiaries of Johnson & Johnson.

In the years following introduction of transdermal fentanyl, fast acting buccal, sublingual, and intranasal forms have been introduced throughout the world - Currently available to the US market is Actiq; a bucally administered lolli-pop lozenge containting fentanyl citrate. Fentora; A simple fast dissolving buccal tablet containing the citrate form of the drug. Onsolis; A fast dissolving buccal film strip containing fentanyl citrate - These are available in generic form with the exception of the newly marketed Onsolis. Buccal IR fentanyl in the US comes in dosages of 100ug to 1600ug, or 1.6mg, and is indicated for use in opioid tolerant individuals with moderate to severe breakthrough cancer pain. No approval as of yet for the products in non malignant pain - meaning any use of this type is 'off label', and typically not covered by insurance carriers.

transdermal fentanyl to daily oral opioids -
dose conversion chart (right click to enlarge) 
The aforementioned long acting and short acting fentanyl preparations have caught on in the US. Transdermal Fentanyl is one of the most commonly prescribed and MD preferred XR opioid products in the US, and is used in patients who have climbed the dosing ladder with other opioids, or experience unmanageable side effects with morphine, etc. The reccomended dosing interval for the patch is every 72 hours, however, transdermal fentanyl was originally studied in end of life/hospice patients - a majority of subjects with compromised metabolism and renal/hepatic function - this considered, the dosing interval for such a subject may not be proper for an otherwise physically healthy subject treated for chronic pain. It was for this terminal care population that Duragesic was heavily aimed for - therefore, many subjects receiving transdermal fentanyl may require either changing the patch every 48 hours, or compensating with increased supplies of a short acting opioid for intermittent pain, which may be increased as needed during points of low fentanyl blood levels.

Because it is a strong opioid, fentanyl is used non medically just as morphine and other narcotics, by opioid tolerant individuals as a means of recreation or simply part of the pattern of habitual drug use. The long acting patch is particularly preferred due to its high fentanyl content; one patch of the strongest dose-size (100ug/hour) contains 10mg of the drug, which represents 100x the standard IV dose. Most of these opioid users apply a portion of the matrix-style patch to the cheek or gums, while those with the gel-style patch remove portions of the alcohol based gel and apply it buccally, make a liquid solution for intranasal or parenteral use, or in some cases swallow it (swallowing fentanyl is very ineffective, as a vast majority is destroyed in the gut/liver before reaching the bloodstream. Casual and experimental users with zero or low opioid tolerance should never use fentanyl by any route outside of the medical setting. Fentanyl is extremely potent and therefore offers little room for dosing misjudgement. An overdose of fentanyl can quickly progress from nausea and sedation to respiratory and cardiac arrest. Overdose of fentanyl by opioid naiive individuals causes frequent deaths among users, most often involving experimentation with the trasdermal patch leading to a massive overdose.

Those who are tolerant to high doses of strong opioids will often use fentanyl recreationally, in which case the optimal route for such use is simply to apply a patch transdermally - after all, the fentanyl patch is intended for opioid tolerant individuals, with the largest providing a morphine equivalent which is upwards of 540mg daily; not to mention the bioavailability of this route is upward of 90 percent, and a patch can last up to 72 hours (3 days). It is important for a user to be well familiar with their personal opioid tolerance, ideally in morphine units, and to equate morphine to fentanyl equivalents either themselves or via literature/internet.

Those who use fentanyl non medically via the transdermal route should never fall asleep until identifying their tolerance to fentanyl; there is typically a 12+ hour lag time between application of the patch and presence of clinically significant blood levels. Not to mention, peak levels are not reached until 24+ hours, meaning if an unfamiliar/naiive user were to fall asleep at some point before reaching significant blood levels (not to mention peak level), overdose may easily occur.

To transdermal users: Be vigilante of the degree of narcosis you feel, especially within the first 24 or so hours of application; if you experience strong effects earlier on in the experience, you could very well overdose by keeping the patch applied; hours worth of fentanyl has already absorbed to your tissue forming a depot beneath the skin, and has yet to release itself systemically (to your bloodstream). If you're already at the point of nausea and somnolence, imagine 12 hours from now when you will have had the >1000ug of fentanyl beneath your skin make it to your bloodstream. In these cases, remove the patch immediately and be sure to have a friend or family member monitor you for the next 12 to 24 hours.

Properties:

Fentanyl is part of a large family of piperidine derivatives, and is specifically a drug with an anilidopiperidine strucure.

Its synthesis is quite simple. N-phenethyl-4-piperidinone (NPP) is synthesized via reaction of 4-piperidinone with 2-phenylethylbromide. NPP is treated with aniline, followed by a reduction with sodium borohydride. This produces 4-anilino-N-phenethyl-piperidine (ANPP), which is then reacted with propionic anhydride to form fentanyl.

Fentanyl produces its analgesic and euphoric effects through its strong binding and agonism of the mu opioid receptor - it shows low affinity to kappa and delta receptors. Its extending N-phenethyl arm enhances binding by reaching further within the receptor complex - This applies to its structural analogues as well. The drug is ~100x more potent than morphine by weight, and ~750x stronger than its relative, pethidine (meperidine). Its doses are measured in micrograms (ug) rather than milligrams (mg) - 100ug of intravenous or intramuscular fentanyl is equianalgesic to 10mg parenteral morphine, or 75mg of pethidine.

Fentanyl is a highly lipophilic opioid; allowing it to quickly and efficiently penetrate the blood brain barrier, as well as attracting it to fat or skeletal muscle tissue. It is the most widely used opioid besides morphine for epidural and intrathecal (spinal) analgesia/anaesthesia - its lipid solubility allows it to A) more easily traverse spinal tissues and more effectively reach and penetrate the spinal cord. and B) distribute itself more directly to an incremental area of the spinal cord and minimally effect other areas/functions.

The drug is metabolized by P-450 enzymes forming inactive metabolites; fentanyl is itself responsible for its effects.

The systemic bioavailability of buccal ("transmucosal") fentanyl - actiq, fentora, onsolis - ranges 50 to 60%, but with a total mucosal absorbtion of around 50% to consider. The bioavailability of transdermally absorbed fentanyl is approximately 90 to 95%, suggesting the drug is not metabolized in the skin. Fentanyl's lipophilicity enhances its absorbtion transdermally - generally, highly lipophilic opioids make good canidates for transdermal delivery.

When fentanyl is administered via transdermal patch, peak blood levels occur from roughly 24 to 72 hours. With continued administration of the patch, steady state levels are acheived around the time for removal of the second patch which is after 4 to 6 days; from here, levels remain consistent with only slight fluctuation, assuming dosage is the same. Buccally absorbed fentanyl reaches peak blood levels at approx. 1 hour post administration.

When injected intravenously, fentanyl rapidly diffuses the blood brain barrier producing analgesia in seconds which lasts 30 to 60 minutes, with intramuscular injection coming on slower and lasting slightly longer. However it is important to be aware that fentanyl's depression of respiration tends to linger long after analgesic effects have passed, this is similar to longer acting opioids and due in part to its lipophilicity & accumulation in tissue. Also useful to note is that peak respiratory depression occurs at 5 to 15 minutes after IV injection (Hospira Corp).

Effects & Side Effects:

Through its activity at opioid receptors, fentanyl produces typical narcotic effects. Effects of fentanyl are much cleaner, or smoother than morphine in quality, owing to its favorably less incidence of side effects - Fentanyl in therapeutic doses has been shown to effect histamine release to a lesser degree than other opioids such as morphine - in studies, doses up to 50ug/kg were shown rarely to produce clinically significant histamine release. Fentanyl generally produces a lesser incidence of emesis (nausea & vomiting) than morphine. Other possible side effects include sedation or somnolence, miosis, constipation, supression of cough reflex, and the possibility of bradycardia. Orthostatic hypotension is possible, and is a result of peripheral vasodilation caused by histamine release.

Centrally mediated effects include analgesia, anxiolysis, euphoria and positive mood, empathetic tendencies and sociability, a sense of contentment, motivation & productivity, and an inhibition of stress/worry and depression. In terms of analgesia, widespread reports and clinical experience suggest a very profound antinociceptive effect. Patients treated for chronic pain commonly rank fentanyl as most effective of all opioids for this purpose.

The pleasurable effects of fentanyl are largely dependent on the route administered - IV injection of fentanyl produces an intense rush and is described as extremely clean in effect. Injected fentanyl will typically produce the warm 'punch in the gut' sensation of hydromorphone, the sudden strange tension of the body followed instantly by a complete/profound release of tension, and generally lacks the often overwhelming pins and needles of morphine considered by some to be uncomfortable.

The overall quality of the fentanyl experience can perhaps best be described by documenting the most commonly reported impressions of fentanyl: Users sometimes report a less pronounced euphoria with fentanyl, and some describe it as simply a happy, content and mellow mood lacking of depression and stress. Some report that the physically experienced narcosis (i.e. body buzz) is more prominent while euphoria is subtle. Some report fentanyl to be more sedating or dreamy and 'nod' condusive than euphoric. Others describe the effects as attributable to heroin.

Sufentanil
 
Basic:

Sufentanil is a potent synthetic opioid analgesic. It is an analogue of fentanyl with about 7x the potency of fentanyl, and is used in the hospital setting under the same indications as similar fentanyl based opioids.

Use:

Use of sufentanil is currently limited to the hospital/clinical setting, where it is used as a strong analgesic and adjunct to anaesthesia.

Sufentanil is used for procedural sedation during routine but painful procedures such as intubation, CSF spinal tap, biopsy, setting of dislocated bones, among others. It is most often administered with a sedative such as a benzodiazapine, usually midazolam.

Sufentanil is used along with benzodiazapines for the induction of general anaesthesia, When given in a weight based dose of 8mg/kg, fentanyl induces deep hypnotic anaesthesia and profound analgesia without any need for an additional induction agent such as a benzodiazapine or barbiturate.

The drug is used additionally as an analgesic component during the maintenance phase of general anaesthesia, given as a continuous infusion by the IV route alongside a neuromuscular blocking agent, a general anaesthetic in volataile or liquid form, and perhaps an additional sedative, along with supplemental oxygen and nitrous oxide. Anaesthesia protocols with enhanced means of airway/O2 management allow for the safe use of much higher opioid doses, which are often required for invasive procedures producing a strong degree of stimuli. Weight based doses as high as 25 to 30ug/kg have been shown to effectively block sympathetic response to surgical stress while maintaining cardiovascular stability and steady blood O2 levels.

Sufentanil may be used for post-operative analgesia by various parenteral routes, given as either fixed doses, continuous infusion, or a PCA (patient controlled analgesia) device.

Sufentanil has been used off label via intraspinal routes. It may be used for post-operative analgesia (via an epidural or subdural/intrathecal infusion), or as a component to regional anaesthesia via these routes in combination with local anaesthetics such as bupivicaine. The high lipid solubility of sufentanil (and all fentanyl analogues in general) allows rapid onset and esay dural penetration, with a lesser degree of respiratory depression. Fentanyl tye drugs however come with several drawbacks by this route; drug distribution is mostly limited to the immediate area of administration, also due their tendency not to linger in CSF fluid, the effects are limited in duration comared to a lipophobic+hydrophilic agent such as morphine. This transient duration is irrelevant when the drug is given via continuous infusion.

After over a decade of success with long acting transdermal fentanyl, researchers have developed a similar transdermal preparation of sufentanil - "TransDUR" Sufentanil, the transdur label is a patent dermal delivery system licensed to Durect Corporation, and may be utilized for additional medications - The available dosage-sizes of these transdermal units will correspond to equianalgesic dosages of the fentanyl patch, but will deliver a continuous dose of fentanyl for an entire 7 days. The patch is currently in development / testing and no release date has been set

Because of its restricted availability, non medical use of sufentanil is rarely heard of. Any unapproved use of the drug is likely to take place among medical professionals such as anaesthetists or surgeons, and perhaps more sophisticated or experienced narcotic users with close friends or family in such a medical position.

Properties:

Suentanyl is a synthetic opioid of the anilidopiperidine subtype. It is a potent fentanyl analogue - Studies suggest it to be approximately 7.5x the potency of fentanyl thus several hundred times more potent than morphine; 12-15ug of sufentanil is roughly equianalgesic to 100ug of fentanyl, or 10mg of morphine, each by the intravenous or intramuscular route. Given in a weight based dosing protocol, literature suggests a sufentanil dose ratio of 1/5 to 1/7 relative to fentanyl.

Sufentanil is a fairly selective opioid. It has (very) high affinity for the mu opioid receptor, and low affinities at kappa and delta receptors.

Fentanyl is highly lipid soluble. Upon IV administration, fentanyl is rapidly distributed within 1 minute, and redistributed within 15 minutes. It has a rapid analgesic onset (within seconds) and an elimination half life of 148 minutes. Sufentanil has a lesser tendency of accumulation than fentanyl, and is rapidly eliminated from tissue, leading to a faster offset of effect and relatively quick post-anaesthesia recovery time. This also lessens the likelihood of delayed respiratory depression, lending favorably to its safety profile.

Effects & Side Effects:

Side effect profile is similar to that of other fentanyl analogues, and typical of mu agonists - the most serious of which may include respiratory depression, sedation, bradycardia, and orthostatic hypotension. Other effects include somnolence, dizziness, constipation, miosis, myoclonus, dry skin & mouth, emesis, urinary retention, and inhibition of libido. Evidence has shown that sufentanil does not produce elevation in histamine levels or cause histamine release; significant pruritis and itching are therefore unlikely.

Like its relatives, when used in the hospital setting these side effects are not likely to be of any relevance; as subjects are typically incapacitated with with other agents, or completely unconscious via anaesthesia.

As it is a potent mu agonist, sufentanil will produce euphoria, anxiolysis, relaxation, subjective warmth, positive mood, inhibition of depression, a care-free state of contentment, and a dreamlike state pseudo-sleep (nodding).

Alfentanil

Basic:

Alfentanil is an analogue of fentanyl, discovered by Jannsen Pharmaceutica in the 1970's. It is an opioid analgesic and is used primarily in the hospital/clinical setting.

Use:

Alfentanil is typically used to provide procedural analgesia & sedation in the Surgical, Emergency, or Critical Care setting. Its short duration of action lend it well to short-lived surgeries or infusion driven protocols with a fast recovery time.

It may be given via injection as an analgesic prior to minor routine procedures such as endotracheal intubation or lumbar puncture along with a benzodiazapine such as midazolam to provide sedation and induce amnesia.

It may be given by injection as a pre-operative sedative/euphoriant to relieve patient apprehension or anxiety which may compromise vitals prior to surgery.

It may be given as a single IV loading dose to induce general anaesthesia along with a benzodiazapine or propofol - AND/OR - may be given as a maintenance agent in general anaesthesia and administered via a continuous IV infusion along with the additional basic components of anaesthesia.

It may also be given for analgesia in the conscious patient, during surgeries using regional/local anaesthesia, in this case usually along with a sedative such as midazolam; both together provide effective sedation and amnesia with fast recovery time and without some of the risks of general anaesthesia.

Numerous anaesthesia protocols using alfentanil are described below:

Alfentanil anaesthesia . For simple conscious procedural sedation; the typical dose range is 5-10ug/kg. For use as an analgesic during short-lived surgical procedures, manufacturer reccomends doses of 8 to 40ug per kilogram. For longer surgical procedures, doses of 50 to 75ug per kg may be used . When used for induction of general anaesthesia, doses of 130 to 245ug/kg are common. Use of alfentanil as an induction agent in adequate anaesthetic doses (130ug/kg) has proven to allow much lower doses of volatile inhalation anaesthetics during the initial stages of surgery. These initial doses depending on the procedure, may be followed by a venous infusion of the drug at an infusion rate of 0.5 to 3ug per kg per minute - Infusions of alfentanil along with a nitrous oxide/O2 combination provides inhibition of sympathetic pain response with a shorter recovery time than traditional 'flurane' agents. Alfentanil provides a similar recovery time as fentanyl.

There have been no documented cases of non-medical or illicit use of alfentanil in the US. Due to its exclusion to primarily the hospital/clinical setting, instances of diversion are likely rare. In the case of recreational use of alfentanil, this would most likely occur among medical professionals such as anaesthesiologists, surgeons, or nurse anaesthetists.

Properties:

Compared with fentanyl; alfentanil is rapid acting with a short duration. It's is less potent than fentanyl (approximately 10x stronger than morphine) - similar in potency to levorphanol or oxymorphone, with 1000ug alfentanil (1mg) being equianalgesic to about 100ug fentanyl, or 10mg morphine, by the IV route.

Alfentanil is a mu-receptor agonist with similar pharmacology to other fentanyl-type opioids; with a high affinity for mu-receptor, and negligible binding at delta & kappa receptors.

Effects & Side Effects:

Side effects of alfentanil may include the expected effects of opioid agonists. Pruritis & itching, peripheral vasodilation, emesis, constipation, urinary retention, dizziness, miosis, and possible myoclonus.

Compared to fentanyl, respiratory depression may occur at to a greater relative extent. Side effects are generally transient in nature, due to its short half life.

Alfentanil produces pleasant opioid-typical effects mediated via the CNS; these are very short lived and include analgesia, anxiolysis, euphoria, relaxation and sedation or somnolence. Patients given the drug however will rarely have the opportunity to fully distinguish or even remember these effects, much less enjoy them - as use of alfentanil is excluded to primarily the hospital anaesthesia setting, and usually administered along with sedatives or anaesthetics, directly before or during procedures.

Remifentanil

Basic:

Remifentanil is a synthetic narcotic related to fentanyl, available in the US as "Ultiva". It is used in medicine much like other fentanyl analogues as an analgesic administered by the parenteral route.

Use:

Remifentanil is available in the US and Canada as the brand name Ultiva, available as a solution for parenteral use. Remifentanil may also be given off label by the epidural or intrathecal route.

The drug is used as a preoperative analgesic or induction agent in general anaesthesia, typically in doses of 0.5 to 1ug/kg per minute by infusion. Single IV loading doses are not reccomended in the absence of endotracheal intubation and cardiopulmonary resuscitative equipment.

Remifentanil is given during procedures as a maintenance agent, typically through an IV infusion, alongside other anaesthetics and assisted ventilation. The reccomended infusion rate is 0.05 to 2ug/kg per minute, depending on the general anaesthetic used, the invasiveness of the procedure, and individual response. In the case of inadequate anaesthesia or adverse sympathetic response to surgical stress, supplemental bolus are reccomended in doses of 0.5 to 1ug/kg, only as needed. As with similar analgesics, adjunctive use of remifentanil in this setting has been shown to facilitate as much as 75% reductions in requirements for volatile anaesthetics & sedatives. Compared to fentanyl and sufentanil, remifentanil may be preferable for short and/or outpatient procedures where a rapid recovery time is ideal - Its elimination is rapid even after long, high dose infusions.

Aside from general anaesthesia, remifentanil is used as an analgesic of choice during minor surgical or diagnostic procedures, given along with a benzodiazepine (typically midazolam).

Properties:

Remifentanil is a potent fentanyl analogue with a rapid onset and offset. It is an opioid agonist with high affinity and selectivity for the mu receptor. Effects at kappa and dela sites are clinically irrelevant.

Peak levels are acheived almost immediately upon administration. Upon slow IV injection, the drug is rapidly distributed within 60 seconds, and redistributed over 5 to 6 minutes, where it binds for a short period with high affinity to mu opioid receptors in the brain & spinal cord.

The pharmacodynamic effects of the drug will correllate very closely with blood levels, more so than with other analgesics. During infusion, response is observed rapidly with any change in infusion rate; steady state levels are reached within 5 to 10 minutes of any adjustment of dose. This allows rapid titration to effect due to precision in dosing, and a desireable safety profile during anaesthesia.

Remifentanil is hydrolyzed by esterase enzymes in the plasma and tissues to form an inavactive metabolite which is excreted via the kidneys; this pathway making up over 95% of its metabolism.

With cessasion of infusion, analgesia will not be present more than 5 to 10 minutes, with the possibility of delayed respiratory depression for up to 30 minutes (generally never past 30 minutes). With remifentanil's limited degree of distribution and rapid clearance, its elimation half life is roughly 3 to 10 minutes. Remifentanil is unique from fentanyl in that its duration of analgesia does not increase with continuous administration. Even after a 12 hour infusion, the drug is rapidly cleared with effects lasting no more than 5 to 10 minutes.

Effects:

Remifentanil produces effects typical of any mu agonist, however with a single dose administration, these effects are transient in nature. Serious side effects may include respiratory depression, orthostatic hypotension, bradycardia and tachycardia. The latter three are most common among the elderly (>65 years), and may occur more frequently than with similar opioids. Other effects typically include sedation, somnolence, emesis, miosis, peripheral vasodilation, muscle rigidity, pruritis, or headache.

The most clinically significant function of remifentanil is to suppress the physiological response to surgical stress (which is mediated via the sympathetic nervous system). Remifentanil (along with other opioids) acheive this via their analgesic actions throughout the spinal cord and brain. In high enough doses, which is possible with the use of intubated ventilation, fentanyl type opioids may produce a deep anaesthetic & unconscious state; effectively blocking nociceptive input to the brain, not to mention inhibiting any degree of physiological response whatsoever to pain.

A reliable account of remifentanil's subjective effects is likely to be rare, as its use is limited to the perioperative anaesthetic setting, and it is often combined with strong hypnotics which produce amnesia.

Remifentanil can be expected to produce euphoria and positive mood as with any mu opioid agonist. The drug has been shown to be highly reinforcing in animals, and may produce more of a rush upon injection than other narcotics. Remifentanil is liable to produce a high degree of physical and/or psychological dependence.


Carfentanil


Fentanyl analogue first synthesized by Paul Janssen's research team.

High affinity opioid agonist with high selectivity for the mu receptor.

One of the most potent opioids known. Strongest opioid available commercially. About 10,000x more potent than morphine and 100x stronger than fentanyl.

Not marketed for human use. Available by the brand name Wildnil which is used in the veterinary setting as an analgesic, anaesthetic, sedative and tranquilizer - mainly in large animals such as bears, horses, lions, giraffes, etc.

Has increasingly taken over the role of etorphine in the veterinary setting due to its favorable therapeutic index and selective pharmacodynamic profile.

Active in humans at around 1 microgram.

High dependence potential. Very high tolerance potential - Continuous use of carfentanyl is likely to produce marked tachyphylaxis (i.e. a an unusually rapid development of tolerance, pronounced with each use)

The Perception of Pain: An Overview of Nociception

The human nervous system is equipped with a complex set of sensory nerves with the specific purpose of sensing threatening or painful stimuli.

pain flow chart
Sensory receptors (nerve endings) are located throughout skin, muscle, bones, organs, and other tissue. A sensory receptor that detects painful stimuli is typically known as a nociceptor. Nociceptors use the process of "nociception" to detect painful situations, encode pain signals and transmit these signals to the central nervous system - up through spinal neurons (delta A and C fibers), on up the spinothalamic tract, and ultimately to key pain processing areas of the brain, to be interpreted by the conscious mind and the autonomic brain; thus triggering a physical and emotional response to pain.

A number of different types of pain receptors (nociceptors) have been identified, each with the ability to sense specific type of stimulus, above a certain threshhold; nociceptors can be classified by the specific stimulus they respond to, whether it be thermal, mechanical, chemical, or somatic (physical damage); the latter of which may only respond to actual injury or trauma.

Basic map of neurotransmission
The primary neurotransmitter involved in carrying peripheral pain signals to the brain is known simply as Nociceptin - A peptide which binds to the nociceptin receptor (NOP-1), generally acting as a potent algetic (pain transmitter) and anxiomimetic (anxiety inducing agent). Substance P plays a role in pain transduction at the spinal and hindbrain (lower brain) levels. It is also involved in the transmission of signals associated with anxiety, and stress.

Several classes of drugs are useful in relieving pain, both non-narcotic and narcotic. Yet almost any effective analgesic, with few exceptions, will directly or indirectly enhance the endogenous opioid system. Furthermore, any effective analgesic has a direct or indirect effect on the process of peripheral or spinal nociception.

Thursday, October 28, 2010

Advantages of Hydromorphone in Sudden Onset and Breakthrough Pain

Hydromorphone in more recent times has been looked upon with favor by physicians and opioid users alike. Most recent literature shows it to be around 4 times the potency of morphine and faster acting. Its quick onset of effects and short duration make it a well suited narcotic for incidents of sudden onset and breakthrough pain. Hydromorphone is best known under the brand name drug Dilaudid.

Dosing and Bioavailability:

Users must consider the poor bioavailability of HM when taken orally. Approximately 25 percent of an oral dose effectively reaches the brain/CNS, compared with about 50 to 60 percent for oral morphine. This factor is important to consider, and dosage should be selected accordingly. An 8 mg dilaudid (hydromorphone) tablet will effectively provide the activity of about 2 mg; making the 8 mg dose roughly equal to a full 15 mg of morphine taken orally - of which around 8 milligrams will become active within the central compartment.

Rescue analgesia in breakthrough pain:
.
Hydromorphone taken orally will take effect in 15 to 20 minutes and generally has a duration of 2 to 4 hours in most users/patients. If the drug is to be taken around the clock for persistent pain, this may require dosing 6 or more (even up to 12) times daily. A better option for continuous symptoms is to use a long acting medication such as morphine ER, taken once or twice daily depending on the formulation; with fast acting hydromorphone as an adjunct for use only AS NEEDED. With a continuous level of morphine in the blood providing a steady baseline level of analgesia, a second agent (hydromorphone) will be required in much less frequency, only for episodes of breakthrough pain which the morphine is unable to prevent.

A well structured approach:

Depending on the individual, hydromorphone may work well in combination with long acting forms of morphine, fentanyl as well as methadone; which when combined with a traditional opiate, may provide a highly effective profile of analgesia due to its additional nmda antagonist properties (which suits it for neuropathic pain as well as exhibiting tolerance sparing properties)

Imagine the pain of a severed arm, or a double compound tib/fib fracture (of the lower leg)...

In the hospital setting, hydromorphone has become a common first or second line medication in the Emergency Department and other units, including the operating suite. In these settings it is most commonly given by IV or IM injection, in doses starting at 1 to 2 mg (titrated upwards prn). Its rapid onset and high potency allows highly effective relief within seconds in severely or critically injured patients. HM's side effect profile is generally less troublesome than morphine, with less histaminic effect (less itching and flushing) and less tendency to produce nausea and vomiting.

Tuesday, October 26, 2010

Gods Own Medicine [Part III]: Opium . Where it all begins


God's Own Medicine Pt III - Revised

Opium Poppy cultivation in Kandahar Province, Afghanistan
What is Opium?

Opium is a naturally occuring latex produced biochemically within the seed pod walls of the opium poppy; a flower which is known by its botanical name papaver somniferum. Opium occurs throughout most of the plant, but is most highly concentrated within the walls of the seed pod, reaching peak levels shortly after the flower petals have dried and fallen from the plant. Opium has a long history of use dating back to ancient times, long before the pharmacological advances which facilitated the extraction of its derivatives. It has has been historically used therapeutically and casually for its analgesic, anxiolytic, antidepressive, and soothing euphoric properties.

Morphine is the primary constituent of opium and was the first pscyhoactive alkaloid ever extracted from a plant source. It generally occurs in concentrations up to 12 percent; however many plants have been bio-engineered by the pharmaceutical industry to produce morphine at concentrations as high as 20 percent or more. Aside from morphine, opium contains modest concentrations of codeine and thebaine. Thebaine produces no narcotic effects and is not directly used in medicine, but its molecular structure makes it useful as a precursor for the production of many semi-synthetic narcotics, some of which are analogues to morphine and codeine.

Production

The opium poppy can grow in any area with a reasonable climate, and is cultivated in Europe, North America, and elsewhere as strictly a garden flower or as an opium source for personal use.

Opium is mass produced mainly in countries throughout the Mid-East, Far-East, and the South Pacific, where peasant poppy farms produce opium clandestinely for the illicit market, or authorized farms operate under contract with pharmaceutical and chemical firms (these include the American companies Mallinckrodt and Johnson & Johnson).

Opium is the crude starting source for many opiates both licit and illicit. The term "narcotic" is classicaly used to refer to the natural, synthetic, and semi synthetic compounds with opium-like properties. The broad term "opioid" may be used interchangeably with the term narcotic. All natural or semi synthetic morphine-codeine analogues rely on the opium poppy for production; more specifically, crude opium latex, or concentrated poppy straw. Initially, morphine and thebaine are extracted from the latex or plant material, and then either refined as is, or further processed to produce semi synthetic narcotics. More on this below.

Harvest and Manufacture:

The traditional method of gathering opium from poppies involves slicing shallow incisions into the wall of the seed pod and allowing the fluid to slowly ooze from the incisions eventually drying, forming a thick solid or gum-like substance. This method has been used for many years, but is quite labor intensive and often leaves portions of unused alkaloid content within the plants. In India, this aforementioned method is used by farmers to supply crude opium for pharmaceutical use. An in depth look at licit Indian opium production can be found **here**

Following extraction of the harvest, peasants can make use of the remaining straw in a number of ways; the seeds are removed from the pods and contracted for culinary use, or sewn for the next harvest. The dried stalks and pod material (i.e. poppy straw) are often sold to small business or licensed chemists; who extract residual alkaloid content for use in their own products; generally mild opiate based tinctures, elixirs, or pills.

A more modern production method is used in Tasmania, and technically does not require "opium", per se. This method involves mowing and grinding the entire plant and processing the straw into an alkaloid rich concentrate of poppy straw (or CPS). CPS is then shipped to drug manufacturing facilities where morphine and thebaine are isolated and extracted; the morphine may be used in morphine medications, or may be further processed (as with thebaine) into other opiates including codeine. This process may be applied to the traditional opium poppy, or the patented 'thebaine only' poppy - In either case, the alkaloids are extracted directly from the straw, and further processed to pure opiate compounds.

Morphine is Processed To:

Morphine Medications, Codeine, Heroin, Hydromorphone, Nicomorphine

Thebaine is Processed To:

Hydrocodone, Oxycodone, Oxymorphone, Oripavine, Etorphine, Buprenorphine, Dihydroetorphine

Codeine: Occurs in such small amounts that it is not regularly used. Most pharmaceutical codeine is produced from morphine; Codeine is a methylated version of morphine (Also known as Methylmorphine)

Use and Effects

The effects of pure opium are primarily the result of morphine and codeine content. One gram of raw opium may commonly contain 60 to 120 milligrams of morphine; with the lethal dose range being 120 to 250 milligrams. Typical opioid effects are experienced; Sedation, somnolence, itching, flushing, anxiolysis and analgesia, euphoria and increase in mood, miosis (pin pupils), supression of cough reflex, constipation and decrease in sexual function. Opium may be either swallowed in raw-solid or liquid form, or smoked. Smoking the substance allows it to rapidly reach the brain within seconds, however, much of the substance is destroyed by heat and secondhand smoke.

Poppy Tea - A Practical Alternative

For peasant farmers in Asia or elsewhere, there is another possible use for the aforementioned plant material, which could be quite lucrative. Dried poppy staw (referred to by many simply as "pods") have become a popular opiate source for american and european narcotic users, typically in the form of a tea.

The dried material (stems included) is chopped and ground into powder, also known by some as "Doda". The powdered straw is then steeped in hot water and (often slightly acidified with lemon or lime), extracting the alkaloids. The solution is strained and then ready for use. It may be prepared with sugar or honey to mask the taste, which users report as very bitter and earthy. Poppy tea is usually light brown to off-white or yellow in color. Poppy tea contains a full spectrum of alkaloids. The desired effects are similar to that of raw opium, and are produced mainly by morphine and codeine. Poppy tea takes effect within 30 to 60 minutes and generally last 6 to 8 hours, though some commonly report effects which linger well into the next day. Effects include the usual anxiolysis, relaxation, positive mood & euphoria, somnolence, body high, itching, flushing, miosis, nausea or vomiting, constipation, and respiratory depression.

Poppy Seed

Many of the poppy seeds used in culinary and baking originate from pharmaceutical crops. The seeds themselves contain trace amounts of morphine and codeine on their surface, which may be present in very small to very significant quantities, depending on how well the seeds were cleaned. In addition to the seeds themselves, the product generally contains alkaloid ridden, unsifted plant matter especially when sold in bulk. Poppy seeds can be obtained in bulk quantities of one or several kilograms; and using the same process used with poppy pod tea, the alkaloids can be leeched from the seeds. The finished product is a tea similar to that of pod tea, with the very same type of effect. Seed extract tea may be just as potent as pod extract tea when large quantities of dirty seeds are used. 
 

Monday, October 25, 2010

Morphine Ketones Vault

Vintage Dilaudid Advertisement
Hydromorphone

Basic:

Known by the popular name Dilaudid. Hydromorphone is commonly used semisynthetic opiate with 4-5X the potency of morphine. Hydromorphone is one of an entire group of ketone based derivatives of morphine. The drug was one of many semi-synthetic opiates created in Germany in the first part of the 20th century - hydromorphone being created in 1924 and first marketed a few years later. The name "Dilaudid" was given, as to indicate its relation to morphine, similar to the names "Laudanum": the opium tincture product, and "Dicodid": a popular reference to the codeine derivative hydrocodone.

Hydromorphone was first introduced to the US market by Knoll, the original manufacturer of Dilaudid, up until recent years. Name brand Dilaudid is widely used to this day, and is presently marketed by Purdue Pharma, who also manufactures the popular products OxyContin and MS Contin.

Hydromorphone is available in the US (and elsewhere) in the form of fast acting oral tablets, once daily sustained release tablets, oral liquid, rectal suppositories for placement in the butthole, liquid solution for injection by all routes, and a brand name fine powder for use in the preparation of compound products or large volume parenteral preparations (IV drips, anaesthesia, etc).

Use:

Dilaudid tablets - 8mg
Hydromorphone has long gained a respected place in medicine as a first or second line analgesic for treating moderate to severe pain where an opioid is indicated. Hydromorphone is additionally used for the treatment of severe or painful dry cough, stemming from an illness/infection or bronchial irritation due to inhalation of chemical irritants.

Hydromorphone is common in the hospital setting, where it is often preferred over morphine in certain settings: i.e. its higher potency - allowing for a lesser volume of liquid when injection routes are used, in cases where patients respond inadequately to morphine or suffer intolerable nausea, pruritis, etc. Its superior lipid solubility, allowing a rapid onset of effects, or higher selectivity of tissue distribution in cases of epidural or intrathecal administration (spinal routes), and its short half life allowing rapid recovery from the effects in cases of short-term hospitalization such as ER visits.

Hospitalists often take more confidence in using hydromorphone over morphine due to its greater potency, as a typical dose of hydromorphone gives the illusion of seeming a smaller dose than the equivalent amount of morphine. for example: many physicians would feel more comfortable giving 1 to 2 mg of Dilaudid as opposed to a 5 to 10 mg dose of morphine, despite the fact that 1-2mg Dilaudid is equianalgesic to 5-10mg morphine - it simply feels less excessive

Hydromorphone is used in the management of both acute and chronic pain on an outpatient basis, typically in oral form. Hydromorphone brand name tablets (Dilaudid) or generic tablets in traditional standard release form have long been available and are used in treating acute or intermittent moderate to severe pain, such as postoperative pain, post trauma or injury pain, severe headache, dental pain, or breakthrough pain incidents in patients taking a long acting opioid such as MS Contin or transdermal fentanyl. When treating incidents of breakthrough pain in the aforementioned patient population, hydromorphone is particularly useful - its high potency allows the drug to adequately meet the demands of those with a significant pharmacological tolerance for opioids, such as those treated with long acting fentanyl, oxymorphone, or methadone. The fast acting nature of hydromorphone in general suits it well to the nature of sudden onset or breakthrough pain incidents.

With the more recent introduction of a brand name long acting hydromorphone tablet (Exalgo), hydromorphone is now more effectively used for around the clock maintenance of chronic pain conditions both malignant and non malignant. Prior to the reintroduction of long acting hydromorphone tablets, there was no practical option for hydromorphone in around the clock pain control; immediate release preparations such as dilaudid were poorly suited for this purpose due to the short half life of hydromorphone. The drug would require dosing as frequently as every 2 to 3 hours to effectively keep pain at bay, which required amounts of up to 12 (sometimes more) tablets daily, and often several hundred tablets on a monthly basis. With the US introduction of Exalgo, once or twice daily dosing is now possible.

Hydromorphone like other opioids, is used non medically by experimental users, casual users, and "narcotic addicts", many of whom self medicate with the drug for various purposes. When used by either informed or habitual opioid users it is primarily taken by non-oral routes. As many users are aware of the low bioavailability of the drug when taken orally. Hydromorphone tablets are crushed into powder form and snorted, for a slight improvement of bioavailability. The drug may also be taken rectally, which is most effective with crushed tablets which have been dissolved in water and squirted deep into the rectum. Most regular or heavy narcotic users prepare hydromorphone tablets to a solution for intravenous injection, offering complete bioavailability of the drug.

Properties:

Hydromorphone is a semi-synthetic opiate of the morphine family. It is one of a group of ketone based derivatives of morphine - the parent structure known as morphinone, differing from morphine only with the substitution of a 6-ketone group, in the place of morphine's 6-hydroxyl group. Going one step further, hydromorphone lacks a 7,8 double bond in favor of the 7,8 diHydro feature, hence "HYDROmorphone".

Hydromorphone is an opioid agonist with a pharmacodynamic profile similar to morphine. It binds to mu, kappa, and delta receptors in the brain, spinal cord, and gut. Hydromorphone produces its effects mainly by its interaction with micro (mu) opioid receptors, to which it shows a higher affinity than morphine.

Hydromorphone is far more lipophilic than morphine - thus rapidly absorbed and distributed throughout the CNS & smooth muscle organs. Peak levels in the blood are reached within 30 to 60 minutes when taken orally, with a half life of 2 to 3 hours; this is much quicker than with morphine. Peak levels are reached within 5 to 10 minutes when injected intravenously, with a half life of roughly 2 hours. Oral hydromorphone undergoes extensive first pass metabolism, it's bioavailability by this route is about 25%. Hydromorphone is metabolized by the same route as morphine, the majority metabolized by uridine diphosphate enzymes to form the inactive hydromorphone-3-glucuronide. Minor amounts are broken down via 6-ketone reduction to form dihydromorphine. The effects of hydromorphone are due to the parent drug itself and not its metabolites. Excretion of the drug is via the kidneys and out through urine.

Effects & Side Effects:

Hydromorphone produces the typical morphine side effects, but is believed to produce little effect on histamine levels. Effects may include emesis, constipation, miosis, pruritis, peripheral vasodilation, physical warmth, a marked release of physical tension (aches and stiffness melt away), and respiratory depression. Compared with morphine, hydromorphone typically produces less nausea, vomiting, and itching, making it an excellent alternative in patients sensitive to morphine, or a first-choice narcotic itself.

Subjective effects with hydromorphone tend to be extremely variable in intensity depending on the route of administration. Taken by the oral or intranasal route, hydromorphone produces a glow similar to morphine but 'cleaner' - many report effects by this route are quite subtle, however this is often explained by an insufficient dose. When taken by the oral route, one may require 4 to 5 fold higher doses than their typical IV dose to produce similar subjective effects. For one who can handle 100mg of IV morphine or 20mg IV Dilaudid, oral doses in excess of 80mg will likely be needed, in the absence of high dose supply, this a subpar route for euphorigenic purposes. Subjective effects include significant relief of pain, a short-lived sense of well being or euphoria, followed by positive mood with positive thought process, a period of enhanced motivation and productivity, increased sociability with a sense of empathy toward others, a vivid dreamlike state, and a relief of anxiety and depression.

When injected by the venous route, the drug produces an intensely pleasant rush which is similar to that of heroin, with many users including myself having a preference for hydromorphone. Hydromorphone's rush is widely regarded within drug-use circles and is often highly sought for this reason alone. It can be best described as a rapid and warm sudden tension of every muscle throughout the body, followed instantly by a release - with every fiber of the body loosening up to a state of complete relaxation, as if the entire body were dying of a thirst which is instantly quenched. An intense almost tingling sense of warmth is felt in the gut (just as pronounced as a kick or a punch; but over a much wider area, and minus the pain of course) as well as the back of the neck and down the spine, radiating throughout the head, and throughout each limb.

As the initial rush of all encompassing opiate intensity gives way to a steady warmth throughout the body (i.e. body buzz), in its wake lies the emotional sense of resolve and state of well being. All stress and psychic discomfort has become contentment. And gradually to surface is a general sense of love, and an almost laughing passion for life. The euphoric or 'happy' sensations surface with such subtlety that it's hard to identify exactly at which point they appeared. One moment they're not present, and suddenly they are.

These effects are quite intense, however will taper off almost as quickly as they appeared. The noticeable effects of oral or intranasally administered hydromorphone last from 2 to 4 hours; when injected intravenously, effects last roughly 1 to 2 hours.

(Like with morphine however, with large doses comes longer duration - effects may last for up to 6 hours with larger doses done consecutively.)

Oxymorphone

Basic:

Oxymorphone is a semisynthetic opiate with a potency 2-7x that of morphine, depending on the route administered. It was discovered in Germany in the early years of the 20th century and introduced to the US market decades later in 1955. Oxymorphone is one among several opiates of the morphinone (ketones of morphine) class, and is closely related to both morphine and hydromorphone. Oxymorphone like its sister hydromorphone is a derivative of morphine however, is manufactured from thebaine, a naturally occurring alkaloid in opium.

Opana ER 20mg Tablets
Oxymorphone is used in american medicine as a potent analgesic, to treat moderate to severe pain where use of an opioid is appropriate. Oxymorphone is perhaps better known by the trade names Opana or Numorphan, the latter of which is used as a generic term for various oxymorphone products elsewhere in the world. It is available as the water soluble hydrochloride based salt; as tablets for oral use either in traditional or sustained release formulation, or as a liquid preparation for parenteral use by the intravenous, intramuscular, subcutaneous or intraspinal route.

This drug has seen an increase in use with the release of the newly formulated OxyContin tablet, serving as a replacement in therapy for the new oxycodone product which is reportedly ineffective for many patients and has received alarming negative feedback. The choice of oxymorphone comes naturally, as first and foremost; many patients treated with OxyContin had been previously switched from MS Contin products due to side effects, preference, or lack of efficacy. In addition, both drugs (oxycodone/oxymorphone) share specifically similar key properties in addition to the fact that with morphine out of the question, Opana ER is the next closest option. The recent spike in the use and popularity of oxymorphone products (primarily Opana & Opana ER) has led to the increasing availability of oxymorphone on the underground market for non medical use. This carries with it the benefit that for many opiate enthusiasts who had previously only heard or read about this previously rare drug, oxymorphone is now likely to be available for purchase. On the other hand however, with increasing availability of an especially potent opioid will come the increasing likelihood that the drug will be introduced to novice users, inevitably leading to overdose deaths.

Mid 1900's - Advertisement for Numorphan
 (Oxymorphone Hcl)
 Use:

Oxymorphone is indicated for the treatment of moderate to severe pain where the use of an opioid is appropriate.

Oxymorphone may be used in the clinical setting for the following indications: acute pain in the emergency room or trauma unit, sedation and analgesia during difficult procedures such as endotrachial intubation or catheterization, premedication prior to induction of general anaesthesia, perioperative analgesia & sedation during procedures in which the physician opts to use regional anaesthesia such as a nerve block rather than put the patient fully under. It may additionally be used for post operative pain control, or as an analgesic in end of life care (hospice). Oxymorphone in the clinical setting is available as a liquid for parenteral use, and is typically given by the intramuscular or venous route.

Oral oxymorphone is dispensed by prescription for outpatient use, and is indicated for the treatment of moderate to severe pain both chronic and acute. Immediate release tablets are typically used for acute pain such as post-injury or post-operative pain, or or as a fast acting analgesic for incidents of breakthrough pain in patients taking long acting opioids such as Opana ER or transdermal fentanyl. Long acting oxymorphone tablets are available as the brand name Opana ER - a twice daily tablet which releases oxymorphone over a 12 hour period - available in doses ranging from 10 mg to 40 mg. Long acting oxymorphone is prescribed for cases of chronic malignant or non malignant pain conditions, in cases where a consistent level of pain control is needed throughout the day/night. For those who experience breakthrough pain with Opana ER, the first choice in many cases is to add the IR equivalent (Opana) to be taken alongside, as needed.

Oxymorphone can be given as a solution
by injection. Image depicts an Opana
injection package.
Oxymorphone like other opioids is sold illicitly for non-medical use, and is used recreationally by casual narcotic users, and habitually by opiate dependents with the intention of self medicating depression, anxiety, etc. Oxymorphone like hydromorphone is a common second choice for heroin users when heroin is unavailable, owing to its high potency and intense rush upon IV injection. One appealing aspect to IV use of the oral preparations is that so little of the tablet is needed for effect; because of its poor oral bioavailability, the tablets must contain 10x the amount necessarry for a systemic (IV) dose, therefore users may take only 1/10th of their typical oral dose for the same effect.

Due to this poor bioavailability when taken orally, most non-medical oxymorphone use is done by the intranasal or parenteral routes, both of which provide far greater systemic availability of the drug. Opana ER or immediate release tablets can be crushed to a powder for insufflation, or prepared into a solution for IV or IM injection.

Properties:

Oxymorphone is a semi-synthetic morphine analogue, typically derived from thebaine. Molecularly, the drug is a hydrogenated ketone of morphine, with a 14-hydroxy substitution; hence the 'Oxy' in the name; with the "morphONE" at the end indicating it as a keTONE. Oxymorphone is molecularly almost identical to hydromorphone, the only difference being the 14-hydroxy opposed to a 14-hydrogen; both drugs share the dihydromorphinone structure. OM is also structurally similar to oxycodone, the only difference being its 3-HO opposed to oxycodone's 3-methoxy - Oxymorphone is produced in the body as a minor metabolite of oxycodone after the demethylation of the drug, however it has shown to play little role in the efficacy of the parent drug. .

Oxymorphone is a highly lipophilic opioid, and is rapidly distributed throughout the brain, spinal cord, and smooth muscle tissue. Peak plasma levels after oral administration are reached at 30 to 60 minutes. Peak plasma levels after IV administration are reached rapidly within 5 to 10 minutes. As most morphine derivatives, oxymorphone undergoes extensive first pass metabolism when taken orally. Oxymorphone's average oral bioavailability is among lowest of the morphine derived narcotics, being roughly 10%, with significant variations depending on several factors - for instance, oxymorphone peak plasma levels have been shown to increase up to 40% when the drug is taken shortly after a light high-fat meal.

Oxymorphone's extensive metabolism includes conjugation in the liver via uridine diphosphate to form oxymorphone-3-glucuronide, and P450 mediated ketone reduction to form 14-hydroxydihydromorphine (Oxymorphol). Analgesic activity is believed to be produced by the parent drug. Its half life after oral administration ranges 7 to 10 hours which is significantly longer than similar opiates; this results in an extended duration of effects and allows less frequent dosing, generally every 4 to 6 hours and in some cases longer. Elimination half life after IV administration is rapid; averaging 1 to 2 hours, with a duration of effects to hydromorphone. The drug is excreted renally and is present in the urine generally no longer than 5 days.

Oxymorphone has pharmacodynamic properties similar to other typical opiates. It is a potent agonist with high affinity at the mu receptor and low affinity at delta and kappa sites. Agonism at the mu receptor accounts for its effects of clinical importance.

Effects & Side Effects:

As a potent mu-opioid agonist, effects are similar to morphine, but several times more potent. Oxymorphone produces narcotic and analgetic effects with a generally kinder side effect profile than morphine. The drug causes little histamine release and therefore less pruritis and itching. Oxymorphone generally produces less nausea and vomiting than morphine. At any rate, side effects may include pupil constriction (miosis), suppression of cough reflex, constipation, somnolence, sedation, muscle relaxation, respiratory depression, and less likely, peripheral vasodilation or itching in some individuals. Clinical tolerance to most of these side effects (including respiratory depression) develops rapidly with repeated use, with the exception of miosis and constipation - these effects do not disappear with tolerance.

Opana 10mg (Pink) &
Opana ER 20mg (Seagreen)
Patients taking Opana ER or short acting oral forms of the drug for pain generally experience good to excellent analgesia with very few side effects compared to morphine. A downside to recreational use by the oral route with a tolerant or experienced user is the need for 10-fold higher doses than would be required with the parenteral route. Many users who try the drug orally do not dose nearly this high, and often conclude the drug is ineffective by this route. The stark differences in oral and parenteral potency will likely present a danger for those unaware of these  specific properties. All this aside, subjective effects of oxymorphone include; a positive mood, increased sociability or empathy, a sense of motivation and productivity, excitement alternating with sedation, a state of dreamlike contentment and vivid thoughts or dreams, inhibition of anxiety or depressive tendencies, and an overall sense of well being. These subjective effects may be quite subtle when the drug is taken orally, however this depends on the dose; whether a modest therapeutic dose, or a higher recreational dose. The potency of oral oxymorphone is approx. twice that of morphine on a milligram basis - This applies only to analgesia.

Intranasal insufflation of oxymorphone offers a fair bioavailability and potent euphorigenic properties. It is typically with this route of administration that one begins to discover oxymorphone's truly potent nature. Users who crush the tablets and snort the powder intranasally generally report a potent, pronounced high which lasts up to several hours depending on dose. Some claim that oxymorphone produces effects like those of oxycodone, typically with a greater degree of sedation, less irritability and less itching; this makes sense given their close structural resemblance.

Preparation of oxymorphone tablets for intravenous injection has been common among heavier opiate users, such as habitual narcotic users who are physically dependent on strong opioids such as heroin, morphine, hydromorphone and fentanyl. Only by the intravenous route does oxymorphone demonstrate its full potential - the drug by this route is approximately 6.6 times stronger than morphine (in vivo), requiring an IV dose of only 1.5 mg of oxymorphone to produce effects similar to 10 mg of injected morphine.
 
 
 

Codeine Family Vault

Table of Contents


(1) Codeine
(2) Oxycodone
(3) Hydrocodone
(4) Dihydrocodeine
(5) Ethylmorphine
(6) Benzylmorphine
(7) Thebacon
(8) Chemistry/Structure
(9) Images


Codeine

Basic:

This drug is a naturally occurring alkaloid present in opium latex derived from the seed-pod walls of the opium poppy; or papaver somniferum. Codeine is an opiate analgesic, and is among the four major components directly extracted from opium; the other 3 being morphine, thebaine, and oripavine.

Codeine was first isolated and identified in 1832 in France, and set the stage for a new generation of codeine based elixirs and patent medicines. Codeine based products were appreciated as they were safer than morphine products and seemed to carry less risk of dependence or overdose. Codeine today is used in medicine for its analgesic, antitussive, and antidiarrheal properties.

Codeine is an immediate derivative of morphine, specifically, morphine's 3-methyl ether. Though codeine is present in opium in small quantities, most pharmaceutical codeine is manufactured from morphine via a simple methylation process. Alternately; codeine may also be produced from the opiate alkaloid thebaine, or even synthesized from scratch.

Use:

Codeine is the world's most widely used opiate, and is available in most nations of the world. Codeine is used in medicine for the treatment of acute mild to moderate pain, an antitussive to treat non productive painful or dry cough, and as an antidiarrheal for cases of GI disturbance. When used for pain in the US, codeine is primarily used in the acute setting, for short term use in cases of injury or illness - in cases of regular or extended treatment the drug has been largely replaced by its superior semi-synthetic counterparts such as hydrocodone & oxycodone.

The most common use for codeine in the US is the acute treatment of non productive cough, severe diarrhea, or mild to moderate pain related to injury such as fractures, sprains, cuts & burns, as well as pain after minor surgical or dental procedures. Naturally, the use of codeine is common in the outpatient, short term or limited care settings such as Urgent Care/Walk In clinics, Emergency Department, Dental Practice, or Primary Care/Family Practice. Codeine compound products, along with its relative hydrocodone (also via compound products) is the most commonly prescribed opiate in the US for short term, minor outpatient treatment; with small prescriptions for minor ailments (such as 3 to 5 day supplies) accounting for perhaps the majority of this use.

In the US, Codeine is available as the sulfate or the phosphate salt, in a wide variety of formulations for a variety of indications. Common forms of the drug are as follows, relative to therapeutic indication. As an antitussive, codeine is generally available in oral liquid or syrups often alcohol based, alone or in combination with an expectorant, acetaminophen, antihistamines, and other additional agents. Oral liquid codeine products often contain up to five other active ingredients. As an antidiarrheal, codeine is available in oral liquid, tablet, or capsule form in doses ranging from 10 to 30mg, with or without the addition of other active ingredients.

Codeine for analgesic use is available in oral form as drinkable liquids, tablets, or capsules, with doses ranging from 15 to 60mg - these are often compound products which contain additional analgesics such as APAP or NSAIDs, sedatives, antihistamines, skeletal muscle relaxants or other agents. Codeine is also available in single entity products as the phosphate or the sulfate salt - products containing codeine alone as the sole agent are classified under Schedule II of the DEA's controlled substance classification system alongside other opioids such as morphine, oxycodone and fentanyl. Due to their less restrictive status, most codeine is prescribed in the form of combination products, which range in status from C-III to C-V depending on dosage and concentration of the particular product.

Products with a C-V classification are in some states permitted for over the counter sale at pharmacies, in a similar fashion to the availability of pseudoephedrine products, requiring a consumer signature and state ID, with a limit on quantity per purchase/per month. Cases such as this are rare in the US, and in states which permit, sales are left to the discretion of the pharmacist; many of whom are unaware that over the counter sale of the drug is legal in their particular state. Availability of OTC codeine products is much more common elsewhere in the world (Canada for example), where the drug is available in low doses ranging from 8 to 15mg per unit compounded with additional analgesics such as acetaminophen.

Codeine is available as liquid solutions for injection by the subcutaneous or intramuscular route, but is not indicated for the intravenous route due to the likely occurence of an anaphylactic reaction potentially leading to death.

Codeine is very effective when taken orally, but may also be taken intranasally (snorted) or rectally, in addition to the previously mentioned parenteral routes (SC or IM). Most recreational use occurs via the indicated oral route, due to the presence of additional ingredients commonly present in codeine products.

Properties:

Codeine is an analogue of morphine with a 3-methyl substitution in place of morphine's phenolic 3-hydroxyl - this change constitutes 2 major differences from its parent. A) Potency is reduced by about 10x and B) Oral efficacy is improved by about 3x, giving codeine an oral bioavailability of approximately 90 % (relative to morphine's ~30-40 % bioavailability). This allows more precision in dosing and convenient titration as compared to morphine, while reducing its liability for dependence and 'abuse'.

Codeine once administered serves the role of a prodrug for the systemic delivery of codeine-6-glucoronide, morphine, and other minor glucoronic metabolites - C6G is a primary active metabolite accounting for 70 to 80 % of a given dose, while morphine accounts for 5 to 10 %. Conversion to its various metabolites occurs in the liver, while excretion takes place via the kidneys. Codeine has an elimination half life of approximately 2.5 to 3 hours.

Codeine, C6G and morphine interact mainly with mu opioid receptors in the brain and spinal cord. Effects are morphine equivalent in nature, however much less potent. The drug is the prototype for a class of mild to moderate strength opiate analgesics and antitussives; codeine and its derivatives have particularly useful properties in treating cough as well as diarrhea.

Codeine has a modest potency, and is among the weaker of the opiate analgesics - the relative potency ratio of oral codeine to morphine is 6/1 (codeine/morphine) respectively. By the parenteral routes (SC or IM), codeine is approximately 1/10 as potent as morphine. Codeine injected intravenously is known to cause a massive release of histamine, with peripheral vasodilation which may lead to profound hypotension and death.

Effects:

Codeine generally produces a larger degree of side effects relative to other opiates. Effects particularly common with codeine tend to be pruritis and itching often accompanied by rash or redness (due to histaminic activity or peripheral vasodilation), nausea and vomiting, drowsiness, dizziness, and constipation. Like all opioids, codeine causes respiratory depression. Codeine tends to cause often overwhelming side effects, even in therapeutic doses. And it is because of these side effects that single doses of greater than 60mg are not used (medically), and a daily upper limit of 360mg is not advised. It is for this reason that some users avoid codeine due to its particularly ''dirty" profile of side effects.

Some users enjoy the subjective effects of codeine, however due to its low potency is generally not suited for those with a significant opioid tolerance such as habitual users of stronger opioids. For those with a non existent to low tolerance, codeine can produce subjective effects similar to other opioids. Commonly: sense of well being or euphoria, positive mood, anxiolysis & relaxation, increased sociability and a sense of empathy, a sense of energy and motivation promoting productivity - or alternately somnolence, sedation, and a dreamlike state. Codeine as well as the family of codeine derivatives in general, tend to produce more 'kick' or pronounced 'buzz' than the morphine family. Additionally there tends to be a lesser degree of sedative quality with a higher degree of uplifting or stimulating qualities. This may or may not be the case with codeine itself depending on the user, but generally does apply to the codeine class of narcotics in a general sense.

Oxycodone

Basic:

Oxycodone is a semi synthetic opioid of the codeinone sub-class and is manufactured from opium derived thebaine. Oxycodone is a structural analogue of codeine, and is related closely to the opiate hydrocodone, specifically as a sibling. The drug's clinical efficacy is comparable to that of morphine, however weaker. The drug was developed in Germany shortly before the second decade of the 20th century (1916), and is available in a number of countries including the US, and widely used as an intermediate strength analgesic. Oxycodone in the last 20 years has developed a controversial reputation of use throughout the US, due in part to the media & public attention which was brought to the drug as a reaction to increased recreational use and dependence associated with the novel-formulation oxycodone product, OxyContin.

Use:

Oxycodone has a long and succesful history in therapy alongside morphine and other opioids, the drug has been in clinical use since 1917.

Some individuals mistakenly make the assumption that the drug is a relatively new narcotic which is somehow distinct from other such drugs - many had been unaware of its existence prior to the late 1990's when the product OxyContin appeared on the market and in the media. The drug had long been available in combination tablets such as percocet and single-entity immediate release form, however the clinical use of opioids in the treatment of non-malignant pain had not yet become mainstream, and many only became aware of oxycodone's existence during the late 1990's and early 2000's with the widespread public outcry secondary to the misuse of OxyContin; a drug which by many is believed to be representative of the era in which palliative opioid therapy in chronic pain became mainstream. Naturally, many conceive this pattern of increased opioid use in medicine as being secondary to the inception of OxyContin. Many also perceive the prevalence of opioid addiction and misuse as a secondary effect to the marketing of OxyContin - Essentially, "OxyContin" was one product which was marketed in the midst of a growing medical and pharmaco trend toward the mainstream & liberalized palliation of non-cancer pain; which naturally fell into the spotlight once attention was brought to the incidental misuse of a myriad of prescription opioids which were now increasingly available in households. By default; prescription drug misuse came to be associated with this one product among many, in which the media took an interest based on its heavy promotion & therapeutic novelty at the time.

Oxycodone is widely used in the US to treat moderate to severe acute or chronic pain both by prescription to outpatients and in a clinic/hospital setting. It is primarily used via the oral route in the US; as it shares the pharmacokinetic properties of the codeine class such as high oral efficacy, it is not indicated for parenteral use.

Oxycodone is available in immediate release tablet, long acting tablet, capsule, or liquid solution, all for oral use. Aside from single ingredient products, oxycodone is widely available as a compounded product containing an additional analgesic such as acetaminophen or an NSAID - compound products contain relatively low doses of the narcotic, ranging from 2.5 to 10mg oxycodone, with up to 325mg of APAP or 200 to 400mg ibuprofen/aspirin.

Oxycodone combination products are as widely used as codeine and hydrocodone compounds such as Vicodin, etc; and are popular among physicians & dentists for relief of moderate to moderately severe pain ranging from acute (dental, trauma, illness, or post operative), to chronic. Oxycodone is often a second choice drug among physicians in treating patients non-responsive or aversive to oral morphine. Clinical experience has shown that oxycodone in equivalent doses is clinically interchangeable with morphine as an analgesic, with neither being superior for this purpose. Oxycodone despite common misconceptions is technically not any stronger than morphine; the drug is simply much more effective orally. The high bioavailability of oral oxycodone makes the drug approximately 50% more effective than morphine by this route on a milligram scale - i.e. 30mg oral oxycodone is equianalgesic to 45mg oral morphine. Systemically, morphine is slightly more potent than oxycodone. ; many individuals simply respond better to oxycodone or experience less itching and nausea, while others respond best to morphine. Equianalgesic doses of oxycodone are as effective as morphine for pain, with limited evidence suggesting that oxycodone may provide more relief in certain cases such as visceral or vascular pain.

The drug since 1995 has been available as the brand name OxyContin - a long acting tablet formulation containing a high content of oxycodone, engineered to release a steady dose of the drug over a 12 hour period. OxyContin is used for the treatment of moderate to severe pain lasting for an extended period & requiring around the clock analgesia. OxyContin tablets have been recently re-formulated by the manufacturer in an attempt to further prevent its misuse - the new tablet is larger in size and engineered in a way which prevents the chewing, crushing or dissolution of the tablets (this is done to defeat the time release mechanism). OxyContin is still available in its original doses of 10, 15, 20, 30, 40, 60, and 80 milligrams, and popularity of the new product is down among both patients and non-patient opioid users.

Single ingredient oral oxycodone is used in the aforementioned forms for treating moderate to severe pain; typically of acute or intermittent nature, such as post operative or fracture pain, and episodes of breakthrough pain in those being treated with long acting narcotics. Perhaps most popular of the fast acting oxycodone products is Roxicodone; a tablet form containing 5(white), 15 (green), or 30 mg (blue) oxycodone, available as the aforementioned brand name or several generic products. The 30mg tablets (small, blue with minimal filler) have become collectively known as 'blues' among users, and are now perhaps the most sought oxycodone product available, by patients and non-patients alike.

Use of the IR product has increased secondary to the release of the new sub-optimal OxyContin product - with many patients switching to the higher dose IR tablets or a new opioid altogether (often Opana ER - long acting oxymorphone). The higher dose roxicodone tablets are about as suited for injection as an oral product can be; they contain minimal filler relative to other tablets and are easily prepared to a fine powder form which can be insufflated intranasally, or prepared for injection via IV or IM routes.

Oxycodone is one of the most widely recreationally used opioids in the US, due to its wide availability, widespread utilization by prescribing physicians, its relation to the more well known narcotic codeine (users tend to perceive the drug by default, as a "stronger-form of codeine") as well as its appeal to casual novice drug users such as those in suburban areas wishing to avoid the stigma of other opioids such as heroin.

Oxycodone is well renowned by opioid users novice and experienced alike, for its well pronounced euphoric properties; oxycodone is highly appealing due to its moderate potency and lack of association with needle use - indeed, oxycodone is known for its ability to retain almost complete efficacy when taken orally, allowing users a pronounced narcotic effect without the use of intravenous or other such routes. Codeine derivatives in general tend to produce more pronounced narcotic effects than morphine derivatives when taken orally. This naturally lends drugs such as hydro-and oxycodone a significant appeal to unseasoned or experimental young drug users.

Properties:

Oxycodone is a semi-synthetic opioid produced from naturally occurring thebaine extracted from opium. It is a structural analogue of the codeine ketone class, and is related to oxymorphone in the same fashion that codeine is to morphine.

Oxycodone is nearly identical to hydrocodone, the only difference being its hydroxyl group (or OH) at C-14 (as opposed to hydrocodone's hydrogen (or H) at this position) Oxycodone is the 7,8 dihydro + 6-carbonyl ketone of codeine. In laymans terms: oxycodone differs from codeine merely with A)a saturation of codeine's 7-8 double bond, B) 14-hydroxyl subtitute in place of simple hydrogen, and C) oxidation of the 6-HO to a ketone. All in all this affords a compound which retains the oral efficacy of codeine, with a potency of 6.5x greater than codeine (slightly lesser than that of morphine), with a cleaner effect profile than codeine.

Oxycodone's mechanism of action is qualitatively similar to that of morphine, which involves the central nervous system and smooth muscle organs/tissue. It produces analgesia and euphoria via agonist activity at mu, delta, and kappa receptors.. It's affinity at the mu receptor is roughly 1/10 that of morphine. Most effects of clinical or recreational value are mediated via its interaction with mu opioid receptors throughout the brain and spinal cord. Its duration of action is equivalent to that of morphine, analgesia & euphoria lasts 3 to 4 hours.

Oxycodone is extensively metabolized in the liver via the cytochrome P450 enzymes. 3A4 N-Demethylation accounts for most of its breakdown, forming noroxycodone, noroxymorphone, and noroxycodol; while 2D6 O-Demethylation to oxymorphone or 6-ketone reduction to oxycodol/oxymorphol accounts for a much smaller scale of its conversion. Oxycodone & its metabolites are primarily excreted renally. It's terminal half life is 3 to 4 hours, typically leaning toward the latter.

It was once debated whether the effects of oxycodone were produced through the parent drug, or one of multiple metabolites, namely oxymorphone. Indeed the effects of codeine & hydrocodone are mediated to a large extent by their metabolites. More recently however it has become apparent that oxycodone's clinical & subjective effects are produced by the parent drug itself; this now being the general consensus within the clinical community.

Effects:

Oxycodone produces similar effects to morphine, physiologically and subjectively. Oxycodone produces analgesia, anxiolysis, a pronounced state of euphoria & sense of well being, positive mood and a sense of optimistim, marked increase in sociability & empathetic tendency, commonly a sense of productivity and motivation. Oxycodone has the tendency to cause a lesser degree of sedation than other opioids, its remarkable ability to trigger motivation and produce empathetic social tendencies is particularly pronounced, relative to other opioids, which lends to its popularity among users. In high doses it is often sedating and dreamy similar to other opioids, with an ability to produce somnolence (nodding out) and the sleep/wake/dream state which is common with narcotics.

Some users prefer to inject oxycodone, typically intravenously. Injection of oxycodone produces a clean and euphoric rush, and lacks the often overwhelming histaminergic (pins & needles) effect of morphine. Oxycodone is relatively weaker than morphine when injected, by about 50% (i.e. 15mg IV oxycodone = 10mg IV morphine), however its distinguishing subjective properties become all the more apparent via this route; the most significant difference is felt in the initial rush, after which point the typical oxycodone glow gradually takes over.

Oxycodone produces an overall 'glow' which is soft, clean, and well defined. Oxycodone's particular 'flavor' is perhaps most similar to hydrocodone.

Oxycodone is liable to produce any and all side effects typical of the opioid class, including sedation, pruritis with itching, nausea & vomiting (emesis), hypotension, miosis, constipation, urinary retention, and respiratory depression - however, oxycodone tends to cause less nausea/vomiting, and pruritis/itching than morphine, and for many users is simply more tolerable (and subjectively 'nicer') than morphine in general.

Hydrocodone 

Basic

A semi synthetic opioid. Hydrocodone, or 'dihydrocodeinone', is a narcotic of the codeine type class and is generally derived from the opiate alkaloid thebaine. Hydrocodone is an offspring to codeine and a sister to oxycodone . The drug was developed in Germany during the 1920's and is available in the US and elsewhere throughout the world - It is one of the most commonly used opiates within the US for its analgesic and antitussive properties. Hydrocodone was one of several moderate strength codeine derivatives developed in Germany during the early 20th century, primarily in search of effective antitussives which lacked the addictive properties of morphine and heroin.

Use:

Hydrocodone is used in the US (and elsewhere) primarily as an analgesic or antitussive; in terms of efficacy; it ranks near the mid-range as an opioid analgesic and ranks among the highest as an antitussive, higher than codeine and lower than its o-demethylated derivative hydromorphone.

In the US, hydrocodone is available only in combination with one or more additional compounds - hydrocodone itself in single entity form is a highly restricted schedule II opioid, however CSA policy allows a less restrictive schedule III listing for HC combination products containing no more than 15mg hydrocodone, and one or more additional agents in a recognized therapeutic quantity. The presence of acetaminophen & NSAIDs in these products therefore fulfills the following roles - a) deters excessive consumption or "abuse", b) creates drug synergy allowing for a lower dose of opioid, and c) meets criteria to qualify for the lower C-III control status (increasing its use by DEA-hyperconscious physicians) thus increasing prescription volume.

Hydrocodone + Acetaminophen Tablets (Blue).
30mg Opana ER (Brown-Red)
 The drug is available for antitussive use as liquid suspensions; among the most popular is 'Tussionex', containing hydrocone in a long acting polystyrene base along with chlorpheniramine, (an antihistamine). 'Hycodan' another popular product, contains hydrocodone along with homatropine, an anticholinergic agent which serves no real therapeutic value and is intended to deter "abuse" (as per reccomendation of the federal controlled substance act) Other brand or generic compounds may which contain a variety of expectorants, antihistamines, or OTC stimulants.

Compounds for analgesic use are typically available in tablet form and include a modest dose of hydrocodone (2.5 to 10mg) along with a typical dose of acetaminophen (325-750mg) aspirin (~325mg) or ibuprofen (200-400mg). Among the original US hydrocodone compound products was "Vicodin" - the first letters represent the roman numeral for 6, reference to the fact hydrocodone is 6 x more potent than codeine (VI-Codin) Containing 5, 7.5, or 10mg of hydrocodone along with a varying high dose range of APAP. These compounds are available under several other brand names and generics.

Hydrocodone's primary role is the management of moderate to moderately severe acute pain. It is one of the most widely prescribed opioids in the US; with perhaps a majority of this use being in the scopes of urgent care, outpatient post op, emergency, or dentistry. It is popular among physicians for fracture pain, post-dental work pain, post operative pain after discharge, kidney stone or gallstone pain, etc. Many physicians prefer hydrocodone products by default, as they attract less attention by patient family members or fellow doctors, carry less restriction and less DEA liability (which unfortunately has come to be a major factor in medical practice today). The drug is also quite common (though not the most fit choice) as an "as needed" analgesic for those with long-standing intermittent pain (migraines, etc), or for treating breakthrough pain in those already treated with long acting opioids such as morphine.

Hydrocodone may be a popular choice for primary care or family physicians; for control of consistent pain in patients until definitive care from a specialist may be secured, or as simply a medium to long-term palliative regimen for a well known & trusted patient who show responsibility with medication.

As of recently: Due to increasing reports of acetaminophen poisonings associated with compound narcotic products, the FDA has recently put a regulatory limit of 325mg acetaminophen per dose-unit. Daily cumulative APAP doses exceeding 4000mg (4 grams) may cause severe liver damage, and should not be used whatsoever in heavy drinkers or those with hepatic dysfunction or disease. With 325mg of APAP per tablet, users must limit their intake to 12 tablets daily or fewer. Depending on the product, this allows a daily total of 60 to 120mg hydrocodone.

Hydrocodone is a popular opiate for recreational use, due to its easy availability and its particularly euphorigenic properties. The drug is most often used orally as intended, as the presence of excess filler and other ingredients effectively deter any attempts at injection or insufflation. Hypothetically however - injected in its pure form, hydrocodone could be expected to produce effects similar to oxycodone.

Opioid dependent users may or may not find value in hydrocodone; dosage must be limited due to the presence of acetaminophen or NSAID's, etc, which limits its utility to those with a high degree of dependence or tolerance. Many users have exploited the hydrophilic properties of hydrocodone via extraction with cold water; hydrocodone dissolves in water efficiently, while acetaminophen along with binders and fillers settle to the bottom of the solution. This method is incorporated for codeine and oxycodone products as well.

Recently as part of a comprehensive government strategy to exterminate illicit RX drug use, 'administrative panels' have made reccomendations to drug enforcement officials to increase restrictions on all hydrocodone products. Hydrocodone compound products will likely within the forseeable future be reclassified to the highly restricted Schedule II status. This will significantly decrease the availability of the drug, both illicitly and therapeutically for those in need of opioid treatment.

 Properties:

Early Advertisement for Hycodan
Also known as dihydrocodeinone, hydrocodone is a semi-synthetic opiate of the codeine type, and is most commonly derived from thebaine. Its molecular structure differs from codeine only in that codeine's 7,8 double bond is saturated (forming the 7,8 dihydro feature); and the 6-position hydroxyl is substituted with a carbonyl feature (making it a ketone, much like hydromorphone, oxycodone, etc). HC is even closer yet to oxycodone; only differing with its 14-hydrogen rather than a 14-hydroxyl.

These modifications make hydrocodone 6 x more potent than codeine, and slightly less potent than oxycodone (roughly 3/4 the potency of oxycodone) 5mg of OC is roughly equianalgesic to 7.5mg HC. HC is roughly half as potent as morphine (40-45%) as an analgesic, with a weaker binding affinity for mu-receptors - taken orally, the two are equipotent by weight (10mg hydrocodone = 10mg morphine)

Hydrocodone (HC) itself is a mu-receptor agonist, and an agonist at kappa and delta receptors to a lesser extent, however it is debatable as to whether hydrocodone itself produces a majority of its effects, or acts primarily through its metabolites.

Hydrocodone undergoes extensive hepatic metabolism. It is metabolized through the same process as codeine - within the liver (via P-450 CYP2D6), it undergoes (most notably) o-demethylation to its morphine counterpart, hydromorphone. As with codeine, there may be inconsistencies in its efficacy in certain populations depending on individual metabolic traits, suggesting a possible role of its metabolites in its overall activity - many individuals lack the cytochrome enzyme required for conversion to hydromorphone (CYP2D6), while others may be extensive cytochrome metabolizers. Being that the 2D6 enzyme plays a role in the metabolism of a number of opioids; 2D6 deficient individuals may require higher doses to acheive optimal benefit, of course this depends whether the drug serves as a pro-drug, or primarily constitutes its own effects. Either way, as a general rule - heavy "workload" for a particular enzyme increases likelihood of drug interactions. Before entering systemic circulation, hydrocodone additionally undergoes N-demethylation, 6-keto reduction, and UGT conjugation. Hydrocodone is well absorbed orally, with a relative bioavailability similar to oxycodone (60-80%). Hydrocodone has a plasma half life of about 3.8 hours, similar to morphine, codeine, and oxycodone.

Effects:

Hydrocodone produces effects which are similar to other mu-agonist opioids. Hydrocodone produces relatively mild side effects compared to codeine, as well as morphine in many cases. Users can expect to experience a degree of pruritis, inhibition of cough reflex, constipation, possible emesis, miosis, sedation, dry skin or mouth, and myoclonus. HC tends to produce less nausea, dry skin, and much less itching/flushing than codeine, which makes this opioid much more tolerable and "clean" than codeine. It also causes less respiratory depression than morphine, and with limits on dosing due to APAP toxicity concerns, significant hypoxia is unlikely unless the drug is mixed with alcohol or sedatives (benzos, barbiturates, etc)

Hydrocodone CNS effects similar to other opioids. Its effects are of morphine origin, and feel particularly similar to oxycodone. Like its 14-hydroxy counterpart, HC is known for its particularly euphoric properties when taken orally. Drugs of this class are special in their ability to retain their pronounced euphoric, narcotizing properties when taken orally. Positive effects include analgesia, anxiolysis, positive mood, a euphoric & lucid state - inhibition of stress, worry, depression, and all things negative - sociability & empathy, a sense of warmth toward others, increased motivation and focus on otherwise tedious activities, and a somnolent-wakeful (nod) state primarily in non dependent users.

With a 3.8 hour half life, the entire spectrum of effects last 2 to 4 hours. It's quite common for physicians to order dosing intervals of 4 to 6 hours, however, many patients find re-dosing necessarry after 2 to 3 hours.

Hydrocodone is underestimated for its ability to relieve pain, analgesic efficacy of this opioid is nearly half that of morphine. HC by weight is equipotent to morphine by the oral route. Hydrocodone relieves pain on roughly the same scale as oxycodone. In an adequate dose range of roughly 10 to 20mg, most users may be surprised at its impact.

Dihydrocodeine (i.e. DHC)

DHC is a semi synthetic opiate derived from codeine. Chemically, it is simply codeine where the 7,8 double bond has been reduced. Dihydrocodeine was invented in 1908, and has become a widely used antitussive and analgesic.

DHC is up to twice as potent as codeine by the parenteral route and slightly longer acting, due to the reduction of the double bond. Hydrogenation of this double bond is said to make the compound more stable - as seen with DHC and dihydromorphine. 

This opioid is effective for most mild to moderate pain, while it is typically only modestly effective for severe pain (less so than hydrocodone), regardless of dose. DHC has seen modest use in the clinical maintenance of opioid dependence. Studies have demonstrated its efficacy and viability as an alternative to methadone or buprenorphine for this purpose. With its mild to moderate strength, it seems DHC would be a prudent choice for maintenance in mildly dependent narcotic users, such as regular users of non injected opioids, or low dose pills such as percocet or vicodin. It would also be particularly useful as part of a stepwise, long term detox regimen - starting with a potent opioid like methadone or buprenorphine, with DHC as an intermediate step before discontinuing narcotics completely. 

The potency of orally administered DHC is marginally greater than that of codeine. 150-180mg of oral DHC is about equal to 30mg of oral morphine; while 60mg of parenteral DHC is roughly equal to 10mg of parenteral morphine. 

It is metabolized by the liver through the same pathway as codeine; by cytrochrome P450 enzymes (2D6 and 3A4), and conjugation (glucuronidation). Most of a given dose is conjugated to form dihydrocodeine 3 or 6 glucuronide. A minor portion of a dose is O-demethylated forming the potent metabolite dihydromorphine (which further undergoes conjugation). The compounds which likely mediate the drugs' effects are dihydromorphine, dihydrocodeine itself, and dihydrocodeine-6-glucuronide. Most of a dose is excreted renally, appearing in the urine.

DHC is typically given by the oral route. Effects are similar to (albeit stronger) than codeine and last from 4-7 hours after oral use.

Parenteral use is acceptable, with the exception of venous injections; dihydrocodeine may cause a dangerous systemic flooding of histamine, severe hypotension, circulatory collapse & death. 

About twice as potent as codeine by both the parenteral route. It is not much stronger than codeine by the oral route - this may be due to substantial first pass metabolism and low bioavailability; one study found the b/a of oral DHC to be as low as 21%. 

Dihydrocodeine is a schedule II controlled substance in the US in its pure form, while compound products may be designated CIII through CV. It is available around the world as oral preparations containing DHC alone, or in combination with acetaminophen, caffeine, phenylephrine and other non-narcotics; usually prescribed for pain or cough. A typical oral dose of DHC ranges, as little as 10-20mg or as much as 30-60mg. DHC is marketed in some countries as "DHC Continus" - a slow release (8-12h) tablet containing dihydrocodeine alone; in doses of 60, 90 and 120mg. It is also available in liquid compound preparations with multiple non-opioids; usually given for cough. 

Ethylmorphine (i.e. Dionine)

Ethylmorphine is a weak semi-synthetic opiate and an analogue of codeine, discovered in 1884.

It has been used for the same indications as codeine - as a painkiller, antitussive and an antidiarrheal. It has a limited but documented history of use in ophthalmology (eye specialty), given to shrink the pupils and produce sedation/analgesia during procedures on the eye. It has been mentioned as a maintenance agent for narcotic dependence, though limited documentation is available regarding this practice.

Typical doses range from around 5-15mg (for diarrhea or cough) to 30-60mg (for mild to moderate pain). Its effects are essentially indistinguishable from those of codeine.

Though not currently available in the US for medical use, ethylmorphine is a schedule II controlled substance in the US in its pure form, while compound products may be designated CIII through CV. 

It is the ethyl-ether of morphine, containing an a 3-ethoxy as opposed to a 3-methoxy (as does codeine). There is very little difference between the two. Ethylmorphine is only marginally stronger as an analgesic than codeine (if any stronger at all).

The metabolism of both is similar. Both undergo 3-dealkylation, to a small extent, by the liver to form the 

much more potent metabolite, morphine. Other routes include 3,6 conjugation and N-dealkylation. Ethylmorphine-6-glucuronide and morphine are likely responsible for the effects.

Benzylmorphine (i.e. Peronine)

Semi synthetic opiate and an analogue of codeine. Benzylmorphine is about 90% as potent as codeine, owing to the bulky presence of a 3-benzyloxy group (as opposed to the 3-methoxy group of codeine).  

It has been used in eye surgery (opthamology) to induce miosis and analgesia/sedation. It is infrequently used and is now classified as a schedule I controlled substance in the US.

Its metabolic and elimination profile is similar to codeine. Its effects are similar to codeine as well, which predominantly include analgesia, euphoria, sympathetic inhibition, miosis and constipation.

Thebacon (i.e. Acedicon, Diacodin)

Semi synthetic opioid similar to hydrocodone. Thebacon is useful as an analgesic & antitussive.

Chemical name is dihydrocodeinone enol acetate, or acetyldihydrocodeinone. Derived from thebaine. A 6-acetyl derivative of dihydrocodeine containing a 6,7 double bond. Often considered a derivative of hydrocodone, which is technically true. Thebacon is produced from thebaine. Available as the hydrochloride or bitartrate salts.

Narcotic potency lies between hydrocodone & morphine. Roughly equal to oxycodone in strength. Slightly stronger than hydrocodone as an antitussive. Antitussive dose is about 5mg orally, or up to 10mg in severe cases. Analgesic dose is expected to be slightly lower than that for hydrocodone, similar to oxycodone - i.e. 10-20mg orally, or slightly less so by injection.

Being a less polar compound; thebacon is likely more lipophilic than hydrocodone and somewhat faster acting. Effects last 3 - 4 hours, similar to morphine.

More euphoric than morphine. Effects are similar to hydrocodone and include analgesia, excitement, euphoria, anxiolisis, sedation, respiratory depression, itching & miosis. Less constipating than morphine, less sedating than morphine. May produce a greater 'rush' than morphine or hydrocodone upon injection.

Tolerance develops at a similar rate to morphine. Morphine equivalent dependence liability with long term use, withdrawal is similar to morphine.

Substitutes fully for morphine in dependent individuals at a similar dose. In once case, a daily dose of 60mg thebacon substituted completely for 50mg daily morphine, when both drugs were given at the same interval four times daily (or every 6 hours).

Addiction liability is at least as high as morphine. Addiction to thebacon first reported in 1931 - patient began taking 10mg daily by injection and quickly worked his way up to 200mg per day, maintaining at this level for over a year. Another patient began at a dose of 5mg daily. He continued taking thebacon at an escalating dose, for its calming & euphoric effect; working up to 40mg daily. Several times he attempted to switch to eukodal but found oxycodone to be inferior. Eventual withdrawal was severely uncomfortable and required a taper with dilaudid.

Codeine Family (Molecular Structure)