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").

Tuesday, March 29, 2011

"Pain Management": Overview for Friends and Family of the "Chronic Pain Patient"

Chronic pain, as defined by the medical community: Painful symptoms which persist long after the underlying pathology/injury has been treated; or continuous pain of which the underlying pathology is unidentifiable or untreatable, leading to chronic, long term pain.

Initially, when a patient presents with complaints of acute or chronic pain, the ideal goal of the physician is to provide a diagnosis, and identify the cause of the pain. This is often difficult; pain may be a symptom of virtually any condition or injury, and is not always physically identifiable with radiology and scanning technology. However, there are plenty of conditions or injuries with which sources of pain may be identified; such as spinal mutations, rheumatic and connective tissue conditions (arthritis), fractures, herniations, and inflammation etc. In many of these cases, a curative treatment may be possible, including surgical procedures, permanent nerve blocks, short term drug regimens (antibiotics, corticosteroids, NSAIDS, analgesics) and physical techniques such as osteopathic manipulative treatment, excersize and occupational therapy.

During the interventional treatment phase of a painful condition, a good physician will manage the suffering, i.e. painful symptoms, caused by the condition - This is approached pharmacologically, with any one of a variety of medications including NSAIDs, acetaminophen, tricyclic antidepressants, anticonvulsants, local anaesthetics and opioid analgesics. Opioids offer superior relief from the emotional and physical manifestations of pain through both their antinociceptive properties, and their ability to alter the brain's interpretation of pain. Managing the suffering caused by injury or illness promotes a higher spirit, better function, and faster healing.

It is unfortunate that pain, depending on the pathology, may or may not resolve whether or not the original cause has been treated.

Additionally, many conditions such as spinal stenosis, severe arthritis, types of neuralgia or neuropathies, are recurring, life long conditions which can not be 'cured' with interventional approaches.

In a perfect world, the physiological and emotional elements of pain could perhaps be 'managed' with strength and will power alone. "Pain builds character" according to some, of traditional values. Unfortunately our world is far from perfect, and even more unfortunately, living and simply coping with pain alone, only works to a limited degree, a very limited degree. There comes a point where rather than building character, the suffering experienced due to pain will systematically diminish one's character, leading to long term depression, physical disability, and worse, neurological 'hypersensitivity' (central sensitization), caused by an over-excitation of nerve signals which communicate pain, the process of nociception. Long term excess nociceptive activity can cause severe depression, an inhibition of dopaminergic activity within the nucleus accumbens leading to anhedonia, and severe hyperalgesia.

When interventional approaches such as surgery and other aggressive treatments have failed to resolve the pain, and when a chronic condition which is not 'cureable' is the source of continuous suffering, management of the distressing effects of the pain, and relate symptoms, is often the only approach left from a medical standpoint, and in many cases, may be only way to provide such a patient with a decent quality of life. Everyone has the right to freedom from pain; whether mild, moderate, or severe, the psychological & emotional effects of chronic, untreated pain are extremely serious. When pain has made such an impact on a subjects life that sleep, emotions, and basic functions have been effected, then often the concept of a long-term dependence to opioids is a preferable alternative, and at worst, a necessarry evil.

Once it has been established that the pain is not 'curable' and must simply be managed; and that medical treatment should emphasize a supportive or palliative approach, focusing on treating the physical and emotional devastation induced by chronic refractory pain...

Clinical management of pain takes on a multidisciplinary approach, applying a wide range of possible specialists, depending on the goals of the patient and the medical team.
The American Board of Medical Specialties now includes a number of specialist fields with an optional subspecialty in 'pain medicine', which is acquired through a comprehensive fellowship training. Boards with a pain medicine subspecialty include: Anaesthesiology, Palliative Care & Hospice, Physical Medicine & Rehabilitation (i.e. Physiatry), Neurology, and Psychiatry, both of which are certified by the same specialty board.

There also exists a newer group known as the American Board of Pain Medicine. The legitimacy of this particular board is ambiguous, as it is currently not endorsed by the American Board of Medical Specialties, the primary board which oversees the specialty boards. The emergence of this board of Pain Medicine comes with a growing notion within the medical field in which pain, classically known as a symptom, may in itself be considered a disease in its own right. This philosophy is controversial, however, there are currently known illnesses marked by hyperactivity of the nervous system, in which this philosophy may hold ground. Fibromyalgia is one such condition, marked by chronic widespread pain believed to be of neuropathic origin, yet with no identifiable pathology. The pain of these conditions may be of somatic, or psychosomatic origin, yet there is little doubt that such pain is genuine, whether psychosomatic, somatic, pathologically visible or non.

A pain management plan may include physical, behavioral & cognitive therapy, often provided through Psychiatrists, therapists, or Physiatrists. Addressing chronic pain from a behavioral and psychological component may be of benefit to the overall function, self image, and attitude of the patient. A neurologist or psychiatrist may address elements of depression, psychological manifestations of the pain, or the pain itself, through a pharmacological approach, while an anaesthesiologist or palliative care specialist may provide a more aggressive approach of the pain through the pharmacological approach. Any medical specialist with a fellowship training and subspecialty of pain medicine, may provide supporitve treatment for those suffering chronic pain.

A primary care physician or family doctor may play a role in a pain care plan, often the centerpiece of treatment, by maintaining a patients overall health. Family physicians are also qualified to provide pharmacological support for pain, including a regular regimen of opioids, etc. Many family or primary care physicians are comfortable and willing to provide this type of care, as the pharmacological properties of opioids are quite straightforward, and widely understood, from centuries of use as one of the world's most fundemental tools in medicine. With complex issues however, and with advancing states of pain and tolerance requiring large doses of schedule II opioids, many family physicians will prefer to consult with specialists, often handing over the analgesic component of care to a comprehensively trained pain specialist.

The ideal approach will include all of the elements previously mentioned, A balance of psychiatric, behavioral, pharmacological, dietary & lifestyle measures aimed at providing the best possible quality of life for those suffering intractable chronic pain.


Chronic pain is often continuous, lasting around the clock, or may appear intermittently at an unexpected time. Pain may be mild, moderate, moderately severe, or severe. Pain may come on rapidly, or gradually, and may be experienced as dull, sharp, throbbing, deep, aching, tingling, burning, stabbing, itching, or electric-like; these words are often used to describe the quality of the pain, and serve as a valuable diagnostic tool in determining the origin and nature of the pain, such as neuropathic, musculoskeletal, rheumatic, vascular, visceral, etc, thus allowing a specific targeted pharmacological approach.

An opioid is selected based on several elements of the pain, such as frequency, intensity, severity, onset rate, duration, anatomical area, and physical/biological characteristics of the patient. Opiates, opiate derivatives, and opioid drugs, all work in a similar manner and target the brain and spinal cord. They relieve pain by acting on opioid receptor sites, which when activated by an opioid, decrease the flow of pain signals to the brain, and blunting the the brain's emotional/physiological response to the pain, thereby altering the way in which the pain is interpreted. Opioids induce a slight sense of well being and increased mood, by promoting the release of dopamine within the nucleus accumbens, the brain's 'pleasure centers'. This contributes the drug's ability to alter pain perception.


Phenylpiperidines


Table of Contents:

1) Pethidine
2) Prodines
3) Anileridine
4) Ketobemidone

Pethidine (i.e. Meperidine or Demerol)

Pethidine is a synthetic analgesic with opioid and spasmolytic properties. It was discovered in Germany in the 1930's as an antispasmodic agent, which was the original focus of research - it's narcotic activity was therefore not expected. The drug is a 4-phenylpiperidine derivative and is the prototype for this class. Related drugs include alphaprodine, anileridine, ketobemidone, difenoxylate, and fentanyl.

Pethidine has multiple modes of action. Its primary role is analgesia and sedation, through agonism at the mu opioid receptor. Pethidine is believed to additionally act as an anticholinergic, a local anaesthetic, and a dopamine & norepinephrine transport inhibitor. Its noradrenergic effect potentiates opioid analgesia at the spinal level, while its direct action on dopamine levels complements mu opioid activity particularly in the mesolimbic pathways of the brain. It may indeed have particularly euphoric and reinforcing properties. Pethidine has actually substituted for cocaine in cocaine dependent animals.

Pethidine was a blockbuster drug and a first line opioid much like morphine in american medicine - it was widely used up until the last few decades, at which point concerns over the toxicity of its metabolite and the availability of safer, stronger opioids have caused it to fall out of favor for most indications.

In the US, pethidine is referred to as meperidine. It has long been available in various formulations by the brand name Demerol as well as non branded products. Pethidine is currently approved for the relief of moderate to severe pain; procedural analgesia alongside a sedative during colonoscopies, biopsies, or intubation; preoperative analgesia, sedation, or perioperative maintenance analgesia; in addition to obstetric analgesic. Though not an official indication, pethidine is useful in a hospital cetting to reduce 'shivering' in terminal or elderly patients.

Pethidine may be injected by the intravenous, intramuscular, subcutaneous, or intraspinal route, and is availble as a parenteral solution for this purpose; given in doses of 50-150 milligrams (which equates to roughly 6 to 20mg morphine parenterally), usually every 2 to 4 hours as needed. Pethidine can be dispensed by prescription for short term use as 50 and 100mg tablets, or drinkable solutions containing 25 to 100mg per dosing unit. When taken orally, a typical dose may be around 50-150mg every 3-4 hours as needed.

Use of pethidine is now primarily limited to the hospital setting, and only under limited indications. It is given orally, by parenteral injection or infusion, or by intrathecal or epidural injection as a single dose or a catheter infusion; this is all dependent upon the setting in which it is used. Pethidine is [believed to be] less likely to produce smooth muscle spasm and GI issues than are other opioids, making it particularly useful for colonoscopy and labor during childbirth. In the case of either, an intraspinal catheter is often used to deliver the drug throughout the epidural space of the spinal canal - In the case of a C-section, this is often done as an anaesthetic regimen, where the opioid is given spinally along with a local anaesthetic such as bupivicaine, and IV sedatives. In the right dose, this produces paralysis and loss of sensation of the body's midsection and lower portion, hopefully covering the desired site of operation.

Pethidine is a relatively weak opioid, slightly stronger than codeine. 75mg parenterally is equanalgesic to 10mg morphine or 100ug fentanyl. It's oral bioavailability is not well established, but it is believed that 150mg orally is roughly equal to 180mg codeine or 30mg morphine orally.

Prodines (Reversed Ester Group)

Prodine is a racemic mixture of two compounds, alphaprodine and betaprodine.

Prodine is a synthetic opioid of the phenylpiperidine type, closely related to pethidine. Simply reversing the 4-ester on pethidine and adding a 3-methyl off the piperidine ring creates prodine, a compound several times more potent with a favorable profile of side effects.

Prodine is the parent compound for its own class of potent analgesics - i.e. known informally as the 'reversed ester' analogues. Prodine and other reversed ester analogues have a potency and addiction liability similar to that of morphine.

Alphaprodine:

The only isomer used clinically. Known by the names Nisentil or Prisilidine.

Fast acting & short lasting. Optimal analgesic dose is 40 - 60mg subcutaneously, given every two or so hours.

May be given for analgesia or anaesthesia. Generally in the same settings as pethidine, mainly childbirth, dentistry, colonoscopy and similar procedures.

Shorter acting than both morphine and pethidine. Effects last only 1 or 2 hours. It has fewer side effects than morphine & pethidine, and may be less toxic than pethidine.

Produces tolerance, dependence and addiction. Dependence liability is greater than pethidine and approaches that of morphine.

Effects include analgesia, euphoria, sedation, respiratory depression, nausea & vomiting.

Betaprodine:

Stronger than morphine and several times stronger than a-prodine. B-prodine produces effects similar to alphaprodine but is shorter acting and not often used clinically - though it has seen clinical use in settings where its short duration has been of value (i.e. trauma, induction of anaesthesia or childbirth).

MPPP: i.e. Desmethylprodine

O-demethylation of prodine creates MPPP - a major active metabolite of prodine. MPPP at one point was a popular compound for illicit clandestine production, and has a potency of about 70% that of morphine. However, there is a real risk of poor synthesis producing toxic impurities. When a 23 year old student hobbyist attempted to synthesize MPPP clandestinely, he instead ended up with the related compound MPTP, a neurotoxic agent that produced irreversible symptoms of parkinsons disease.

Allylprodine:

Allylprodine is about 23x the activity of morphine due to the presence of an allyl group which binds to an additional target on the mu receptor. Due to its potency, allylprodine would seem a good candidate for the clandestine chemist as a 4-phenylpiperidine type heroin substitute.

Other Prodine Analgogues:

Other reversed ester analogues include PEPAP, MPPP (desmethylprodine), promedol (1950's), prosedol (1990's), and meprodine - This group of compounds ranges in potency from a fraction that of morphine to several times stronger than morphine, at least.

Anileridine

N-aminophenethyl analogue of meperidine developed in the 1950's. Not used in the US and rarely used elsewhere. Given by oral or injection routes.

About 1/2 to 1/3 as potent as morphine when given parenterally, or 2-3x stronger than meperidine - Potency would be comparable to hydrocodone. Shorter acting than morphine. Its effects last 2-3 hours.

Has been used in obstetric analgesia, as a supplement to nitrous/oxygen anaesthesia, and for post operative pain.

Side effects are no more frequent than with meperidine. Respiratory depression is shorter in duration than with meperidine. Typical opioid side effects are common - including itching, miosis, nausea or vomiting & respiratory depression.

Doses of 100-150mg produce definite morphine-like subjective effects in post-addicts which is one study were compareable to 15-30mg morphine. Subjective effects include analgesia, euphoria, excitement or cheerfulness and sedation.

Anileridine will suppress morphine abstinence completely and acts like a typical full agonist.

Ketobemidone

Synthetic opioid and analogue of pethidine; specifically, a hydroxylated ketone of pethidine with several-fold greater potency (roughly 6x).

Acts as an agonist at mu opioid receptors. Some suggest a second mode of action as an NMDA antagonist through its metabolite norketobemidone.

Roughly equal in potency to morphine (1-2x morphine). 5-10mg subcutaneosly is roughly equianalgesic to 10mg morphine, 2mg hydromorphone, or 75mg pethidine.

Takes effect rapidly. Effects generally range from 4-8 hourse depending on dose and ROA (morphine generally lasts 3-4 hours).

Bioavailability of 34%, nearly identical to morphne (33%).

Greater sedative effect than morphine and methadone has been reported in literature.

Effective therapeutic dose has been observed to be lower than effective dose for producing euphoria. May therefore be less reinforcing thus less addictive to patients.taking the drug medicinally.

In those using the drug illicit purposes dependence liability is at least as high as morphine. A particularly severe withdrawal has been observed upon discontinuation.

Effective in extreme pain of long duration, possibly more so than morphine (according to P. Petolta).

Piritramide

Piritramide is a fully synthetic opioid. It is used in some countries, excluding the US, in the treatment of moderate to severe pain. Its most common trade name is Dipidolor.

Piritramide is often given in hospital settings such as critical care/ICU or post-op, typically by the oral or parenteral routes. Chemically, it is a member of the phenylpiperidine family. It is structurally similar to loperamide and diphenoxylate, both used to treat diarrhea.

Its potency (per milligram) is slightly less than that of morphine; 15 mg of piritramide is equivalent to about 10 mg morphine, when given by the parenteral route. It is a long acting opioid and has a half life of 3-12 hours.


Chemistry Series In Laymans Terms Part II of III

Ketones of Morphine and Codeine - Dihydromorphinone & Dihydrocodeinone Series

Diydromorphinone & Dihydrocodeinone derivatives include hydrocodone, oxycodone, hydromorphone, and oxymorphone

Click The Image for a larger visual guide. For the previous chemistry lesson click HERE

Friday, March 25, 2011

PCP Vault

Basic:

Chemically known as phencyclidine. PCP is a psychoactive drug of the arylcyclohexylamine family, and exhibits dissociative-anaesthetic, sedative, and some stimulant properties. It is structurally related to ketamine and produces similar effects, but is about 4x more potent on a milligram basis.

Pharmacology:

Its main mode of action involves the glutamatergic NMDA receptor; PCP is an NMDA receptor antagonist - specifically, it binds to the PCP1 site located on the inner surface of the NMDA complex, and blocks the opening of the ion channel. It also blocks the nicotinic acetylcholine receptor. PCP exhibits some dopaminergic properties; is a partial agonist at the D2 (dopaminergic) receptor, and it is believed to inhibit dopamine reuptake by acting at the PCP2 site located on the dopamine reuptake complex. Dopaminergic action may be involved in its psychotomimetic properties (i.e. its tendency to produce a state which mimicks psychosis).

Due to its blockade of the NMDA receptor, PCP produces a state of dissociation - i.e. a state best described as a disconnection of conscious awareness from sensory and environmental processing. This is due to the inhibition of communication between environmental & sensory input and the processing structures of the brain; and between various circuits of the brain itself - depending on the dose.

Simply put; dissociatives inhibit the complex processing capacity of the brain to translate sensory stimuli into experience or awareness, leaving the "mind" detatched from the senses, the environment, and the reality at hand (or in higher doses, detatched from essential data stored in other areas of the brain pertinent to identity, self awareness, and memory).

Effects:

Euphoria

Body buzz

Increased energy

Megalomania; Feelings of power, fearlessness, and relevance

Increased self confidence and distorted self perception

Temporary motivation, unusual revalations, or the realization of odd ambitions

Dose dependent sedation or excitation.

Analgesia, anaesthesia, numbness, inability to feel pain

A sense of warmth or affection toward others

Social disinhibition; increased sociability or possible chattiness

Distortion and loss of sensory perceptions (dose dependent)

Closed eye or open eye visuals

Intense body buzz

Complete mind/body dissociation in high doses (very bizarre)

Distorted perceptions of reality or loss of self awareness

Amnesia

Slurred speech

Out of body experience

Distorted time perception

Ataxia and impaired motor coordination

Increased heart rate or depression of heart rate, respiratory depression, nausea & vomiting

Further Off-Site Reading: Neuropharmacology of PCP 

Wednesday, March 23, 2011

Dosing Guide for Switching to Methadone or Buprenorphine Maintenance


I've developed a little guide for those interested in buprenorphine or methadone maintenance - Dose ranges of both buprenorphine and methadone and buprenorphine are based off of daily morphine intake (in mg) or daily heroin intake (in 'bags' of average purity). I've taken dose response rates of each drug into consideration, so these should serve as good ballpark figures.

CLICK THE IMAGE BELOW FOR FULL SIZE

Saturday, March 19, 2011

A Drug Legalization Model

Model For The Legalization of Opioids and other Controlled Substances

 Narcotic use is the right of any adult man or woman, just as the right to marriage and sex. Narcotic sales, just as coffee and fast food sales, is the right of a free market, trademark of a capitalist society. Additionally, narcotic sales should be controlled just as alcohol and tobacco sales; simply in the sense of age restriction - sales limited strictly to adults of 18/21 or older, upon verification with ID.


Opium in any form, opium derivatives, semi synthetic opiates, and synthetic opioid drugs - All should be available in retail markets such as grocery, convenience, drug-stores, department stores, chemist shops and supermarkets - Stocked and sold in a similar fashion to over-the-counter cold medicines, vitamins and other supplements (St Johns Wort, Melatonin, Ginseng). One may purchase a 500-count bottle of morphine or oxycodone tablets, just as they would a bottle of nyquil or liquor. One may purchase an express size blister-pack of 12 Vicodin tablets at a convenience store; either for a pesky headache or to mellow the stress and tension of the day - makes no difference. Dilaudid 24-count boxes or generic hydromorphone tablets may be bought on special some weeks, "buy 2, save 5 bucks", just like a sale on Tylenol. Narcotics available safely and cheaply in a retail setting, offering those with severely painful illness to conveniently manage the pain without hassle, or as simply a remedy for depression, stress, anhedonia and melancholy. A remedy for a lonely weekend or cold night outside, a 'helper' for a draining day at work or a peaceful nights sleep. For those of the organic or fair trade type - raw opium tars, tinctures, powders and extracts may be a short stroll down to a natural food or herb shoppe, and stocked on the shelves next to psilocybin mushrooms, coca-products and cannabis strains.

Needles should be freely and cheaply available, along with sterile liquid opioid solutions which are injection-friendly and distributed with warnings, literature and direction. Privatley (not publicly) funded safe drug use/injecting campaigns should target the drug habituate demographic, and provide truthful but objective knowlege about drugs, precautions, their use and effects.

Public safety is a government issue; traffic enforcement should take a similar model to its current state, except rather than the blanket approach of 'blood testing and arresting', allow officers to arrest or cite based on the individuals percieved level of impairment and ability to drive - For example, marijuana remains in tissues for months but does not impair driving ability for more than 2 hours, and certain drugs such as opioids cause little to no degree of driving impairment at all in many regular users. Moderate doses of stimulants such as cocaine may actually enhance ones ability to remain vigilant on the road. Driving should be approached on an individual basis; officers may arrest a heavily sedated and uncoordinated driver, ascertained by the officers authoritative judgement rather than black and white 'testing'. This may be achieved with the use of field sobriety tests such as the 'line walk' and 'nose to finger' excersize.

Drug overdose should be approached in the same manner as alcohol poisoning (aka alcohol overdose), with a paternalistic treatment at the hospital, offers for treatment, and a boot back out the door. When a user fucks up and takes too much causing death, the situation should be treated as what it really is - a bad or uninformed decision with a tragic and seemingly senseless consequence, just as any death related to alcohol poisoning, cancer, heart disease or diabetes. Responsibility for the death by overdose will be removed from Doctors or Street Dealers, and onto the party who is truly accountable - the OD victim.

For clinical use, narcotics may still be prescribed as necessarry for painful conditions - just as ibuprofen or naproxen may be prescribed; while non medical users buy from retail establishments rather than by prescription - Every 'drug problem' of an individual will then be seen in a rational light as to cause and effect, once allowing true responsibility and accountability a place in our culture.

The FDA may or may not remain in place, however regulatory measures would mimic those of non controlled over the counter medicines; and may only dictate the "advertised indication" of a drug, rather than require its federal stamp of approval for commercial sale - a substance not labeled as FDA approved may be marketed, but simply won't be condoned by the FDA; communicating a higher potential of risk. With the FDA operating by the previously mentioned philosophy, it will take on more of an 'advisory & disclosure' role, to provide 'suggestion' and disclose important safety information, without any lawful regulation.

The ONDCP (Office of National Drug Control Policy) and the DEA (Drug Enforcement Administration) will be legislatively abolished along with the repeal of both the Controlled Substance Act (drug scheduling) and the Harrison Narcotics Tax Act. This will unquestionably lead to tax savings of hundreds of billions of dollars annualy, and improved funding for public education and public safety & service such as police patrol and fire/rescue. With more state and local police funding, potential hazards such as impaired driving and consumption by minors will be managed.

Afterthought:

Even better, every federal narcotics agent who is left without work, may be left homeless to rot on the street; like the 'junky scum' he/she used to arrest/abduct for a living.

Friday, March 18, 2011

How Do Psychostimulants Work?

Basic Pharmacology of the Prototypic Psychostimulant:

Most psychostimulants serve as exogenous ligands for the catecholamine transporters - in laymans terms, the presynaptic pumps which vaccum any leftover dopamine or norepinephrine within the synaptic cleft back into storage. The prototypic stimulant in this case binds to the catecholamine transporter, serving two functions:

1) inhibit its reuptake of neurotransmitters.

2) causes the transporter to function in reverse by pumping catecholamines outward into the synaptic cleft. 

The overall increased concentrations of synaptic catecholamines leads to a major increase in catecholamine signaling, inducing arousal of the sympathetic nervous system and increased mesolimbic "reward" activity.

Many psychostimulants (including amphetamine and cocaine) also act as ligands at the serotonin transporter; serving the same function of inhibiting reuptake, and/or reversing transporter flow. In fact, there is an entire family of atypical psychostimulant compounds (which includes most notably MDMA/ecstasy), that exhibit a unique set of empathogenic and psychedelic properties. This has been linked to their relatively potent serotonergic properties.

Thursday, March 17, 2011

Treating RLS

Restless Legs Syndrome
RLS, is also known as Wittmaack–Ekbom syndrome. It is a medically recognized condition characterized by the irresistable urge to move or stretch one's limbs due to odd, sometimes extremely uncomfortable sensations. The sensations are often difficult for patients to describe in words, but are often described as aching, electrical, buzzing, tickling, or antsy sensations felt in the legs or arms. The intensity of the symptoms can range from mild to severe; severe cases may cause a significant impact on their everyday activities, with subsequent sleep loss, drowsiness and fatique, which can be increasingly detrimental to aspects of one's life.
Symptoms of RLS most frequently manifest in the legs, but may also occur in the arms and even phantom limbs. In severe cases, all limbs of the body may be affected, which is typically described as severely uncomfortable.

The underlying cause of RLS is unknown, but most research focuses on the dopamine system and iron levels. This is based on documentation of some succesful treatment of symptoms with iron supplements and levodopa; a centrally acting prodrug for dopamine. Samples of cerebrospinal fluid in RLS subjects have also shown some irregularities in dopamine and iron within the CSF fluid. Symptoms of RLS most often occur at night time/bed time, during which time dopamine levels are at their lowest. Irregularities in the endogenous opioid system may play a role in the condition as well; studies have suggested a possible opioid role in some cases.

One of the first steps in identifying/treating RLS should be bloodwork in order to rule out/check for iron or folic acid deficiencies; approx. 20 percect of RLS subjects may have low iron levels as a contributing factor.
RLS in some cases may be secondary to an underlying condition, these include but are not limited to; magnesium deficiency iron deficiency, diabetes, thyroid disease, peripheral neuropathy, arthritis, and fibromyalgia. Additionally, moderate to severe symptoms of RLS are often present in opioid users during and sometimes after acute withdrawal syndrome.

Certain drugs and medications have been known to also cause or worsen RLS symptoms; these include monoaminergic antidepressants (MAO, SRI, Tricyclics) and antihistamines (diphenhydramine, dimenhydrinate).

Treating RLS Symptoms

Over the counter supplements: Iron, magnesium, melatonin, potassium, folic acid, calcium, vitamin E, st johns wort or simply multivitamins may help in the case of an underlying mineral deficiency,

Over the counter analgesics - acetaminophen, ibuprofen, aspirin, naproxen.

Dopamine agonists may be effective in some individuals: ropinirole, pramipexole, pergolide, rotigotine, carbidopa, levodopa.

Benzodiazapines and Nonbenzodiazepines: diazepam, clonazepam, zolpidem, zopiclone, eszopiclone; these not only help with the physiological symptoms, but help promote sleep and reduce night awakenings.
Anticonvulsants: gabapentin, carbemazepine, these may help especially in those with painful RLS symptoms.

Opioids: Have been highly effective for severe or resistant cases, as well as RLS symptoms related to neuropathic pain conditions; morphine, buprenorphine, hydrocodone, oxycodone, fentanyl. Opioids with NMDA antagonist activity may be especially effective - tramadol, methadone, levorphanol. For those unable to obtain opioids by prescription, a peripherally acting opioid such loperamide (Immodium AD) is available over the counter and can be taken in high doses (> 20mg) to treat RLS.

Saturday, March 12, 2011

Alternatives to OxyContin (In the Treatment of Chronic Pain)

Attention: I advise against improper or illicit use of any opioid. The potency-related information cited on this blog is for harm reduction purposes, and should not be interpreted as an endorsement of legal or illegal drug use. .

Many are disappointed with the new OxyContin tablet...

Since the recent reformulation of OxyContin, efficacy of the new medication has took a plunge. Common issues have included gastrointestinal complaints due to the filler in the tablet, poor absorbtion of the tablet, and cases of tablets being regurgitated or excreted through the bowels fully intact. Perhas the most pressing concern is the reduced analgesic efficacy; with many patients requiring drastic increases in breakthrough medication, within this lies the possibility of many patients being labeled as drug seeking, when a Doctor just doesn't buy that the medication is not working. Indeed, some doctors adamantly attest to the fact that the new formula is exactly the same as the original - I'm not sure what is more disturbing; a doctor who actually believes this, or a doctor who simply misleads a patient about the new drugs effectiveness. I digress.

Switching to long acting therapy with Opana ER (oxymorphone) seems to be an increasingly common reaction for those finding limited relief from the new OP tablet. I believe many patients will see a significant improvement in anagesia with oxymorphone, in some cases even being superior to the original OxyContin. Of course this won't apply to 100% of the population, and knowledge of oxymorphone pharmacokinetics is crucial - there is over a 40 percent recuction in oral bioavailability with oxymorphone compared to oxycodone, and it is critical that the dosing reflects that. An oral dose of oxymorphone should be approximately 10-fold its IV/IM dose. I've written up a simple guide based on available dosages of OxyContin and their corresponding Opana ER equivalents. The manufacturer website has its own digital conversion, however it seems that doses may be underestimated in the name of 'caution'. Both OxyContin and Opana ER are 12 hour formulas, and the listed daily dosages are generally diveded into 2 separate doses, one every 12 hours - With uneven daily doses, a regimen of 3 times daily (q8 hours) will suffice.

Conversion from OxyContin to Opana ER

20mg OxyContin/Day = 10mg Opana ER/day
30mg OxyContin/Day = 15mg Opana ER/day
40mg OxyContin/Day = 20mg Opana ER/day
60mg OxyContin/Day = 30mg Opana ER/day
80mg OxyContin/Day = 40mg Opana ER/day
160mg OxyContin/Day = 80mg Opana ER/day
120mg OxyContin/Day = 60mg Opana ER/day


Note: Some report that the new OxyContin tablets seem weaker than cited above when taken orally. One reader claims "I would just like to state for the record that having tried new OP reformulation, opana er equivalency is 40mg oxycontin equals 30mg of Opana ER." 

I may as well also remind readers that Exalgo (long acting hydromorphone) is another option.

Exalgo is the brand name for hydromorphone long acting tablets, Exalgo is generally taken once daily; every 24 hours. Long acting morphine formulations are available in 12 hour tablet form, or 24 hour capsule form. Exalgo is available in three different strengths, with each strength being roughly equianalgesic to the following daily opioid regimens:

Conversion to Exalgo (Hydromorphone XR) from other long acting Opiates.

Exalgo 8mg: 40mg/day morph ER or hydrocodone . 20mg/day oxycontin . 10mg/day opana ER
Exalgo 12mg: 60mg/day morph ER or hydrocodone . 30mg/day oxycontin . 20mg/day opana ER
Exalgo 16mg: 80mg/day morph ER or hydrocodone . 40 mg/day oxycontin . 30mg/day opana ER

Thursday, March 10, 2011

Salvia Divinorum

Crushed and dried salvia leaf as commonly marketed.
Salvia is a large genus of plants in the mint family, which includes the popular salvia divinorum, also known as "diviners sage". The leaves of salvia divinorum are often consumed for their psychoactive properties, believed to be due to their main active compound, salvinorin A.

Salvinorin A produces psychotomimetic & hallucinogenic effects through its potent agonist binding at kappa-opioidergic and D2-dopaminergic receptors in the brain. Being an agonist at the kappa-receptor, its effects are generally perceived as dysphoric in nature and are not likely to contribute to habituation or addiction. Its effects are short lived and intense. The salvia experience is generally not an experience that most users seek to repeat, but makes for interesting conversation none the less.

Salvia, along with its derivative salvinorin A, have in recent years been criminalized by state law in some areas, but remain legal and available throughout most of the US and world.

Salvia is typically available in crushed or whole leaf form, or as a standardized extract - consisting of crushed salvia leaf which has been treated with a pure crystalline powder form of salvinorin A (thus allowing a known quantity of alkaloid per weight of material). Salvia, in plain leaf or extract form, is usually smoked like tobacco. In other cultures, the leaves have been eaten, brewed as a tea-like infusion, or chewed by mouth like coca leaf (i.e. as a "quid") and absorbed through buccal membranes. The efficacy of traditional oral routes is disputed, as salvia is largely inactivated by the GI tract when swallowed.

Monday, March 7, 2011

A Progressive Approach to Depression

The Monamine Theory of Depression Must Be Challenged 

Depression and Anxiety related illness may have a vast variety of underlying pathology. The mainstream approach is in fran terms, a "One size fits all" approach - a simple solution to a complex issue, which is touted as absolute 'fact'.

Our approaches must be expanded to reflect the intricate nature of the human brain.

As pharmacological science & the medical establishment advances, our understanding of the pathological nature of mental illness has progressed. Research has shown a complex degree of biological elements underlying depressive states; which frankly go far beyond the simple monoamine hypothesis to depression. Mainstream drug companies such as Pfizer market a cookie cutter series of SSRI's and SNRI's, each new drug with the same effect as the last - With advertisements presenting a simplistic and outdated 'monoamine chemical imbalnce' theory as absolute fact. This theory upon which big-pharma continue to fixate is becoming less credible over time, and at best, questionable.

Along with a continuing open minded approach to revisiting the MANY elements of mood and emotion, an important element to focus upon is the endogenous opioid system:

Focusing in part on the endogenous opioid neurotransmitter system can be seen as a single key component which can serve as a building block to a modern, more progressive understanding of depression. Based on the general understanding of the body's endogenous opioid system, we can conclude that new treatments for depressive conditions may start with some of the following opioidergic based therapies.

ERI's or Enkephalinase Inhibitors: Inhibit enzymes responsible for the metabolism of enkephalin. Enkephalins are naturally occuring opioid peptides which act as agonists at primarily delta opioid receptors, in addition to mu receptors, and produce antidepressive effects. An enkephalinase inhibitor works in an analogous way to popular serotonergic antidepressants; essentially by inhibiting the (metabolic) reuptake of these neurotransmitters, allowing higher synaptic levels of the peptide to remain active.

KOR Antagonists: Reverse the effects of endogenous/exogenous kappa agonists; Although certain selective kappa activity may play a role in supraspinal analgesia, agonist activation of the kappa receptor is implicated in profoundly dysphoric and often hallucinogenic effects. In addition, kappa activation is believed to reverse many effects of mu receptor activation; thereby acting as a negative feedback system to mu opioid effects. Therefore, antagonist activity at the KOR (kappa receptor) and neutralization thereof will prevent this negative feedback, as well as enhance positive mu-opioid mediated effects. The opioid buprenorphine in addition to partial mu-activity, is an antagonist at the kappa receptor; this is believed to play a role in buprenorphine's antidepressant properties. Another kappa antagonist, simply known as JDTic is being studied for its antidepressant-anxiolytic (anti-anxiety) effects - JDTic is highly selective to the kappa receptor, and produces its antagonist effects without affecting mu or delta receptors.

DOR Agonists: Agonists of the delta receptor produce modest analgesia, and are believed to possess antidepressive effects. This may be associated in part by increasing production of BDNF, or 'brain derived neurotrophic factor' - BDNF promotes nerve cell growth, and has been shown to play a role in modulating depression in mammals; studies have shown that stress induced downregulation of BDNF leads to eventual atrophy of the hippocampus, a trait which is common among subjects suffering chronic depression. Delta agonists have been observed to stimulate respiratory function in low doses, while producing occasional respiratory depression in ultra-high doses. Delta activity plays a small role in the analgesic properties of some opioids.

MOR Agonists: The ability of opioids to produce analgesia and an emotional state of well being is primarily mediated by agonist activity at mu opioid receptors. Opium derivatives were historically used to treat depression and anxiety related disorders, and were widely prescribed by Physicians for this purpose. Mu opioid receptors modulate our cortical perception of pain, both physical and emotional - Both manifest as through the same states of suffering, which is reduced with MOR agonists. The body's natural opioid peptide endomorphin, is our most potent natural painkiller and antidepressant, and is selective for mu opioid receptors. MOR agonism enhances dopaminergic release within the nucleus accumbens, leading to increased motivation and a state of well being. Antagonists of the kappa receptor essentially accomplishes the same goal; increased mu opioid activity - through a different mechanism. Regularly administered alongside supplemental agents such as NMDA and/or cholecystokinin antagonists, mu selective opioid agonists can succesfully control depression/anxiety without the rapid development of tolerance; the key destructive element behind opioid dependence.

Furthermore, three known variants or subtypes of the mu opioid receptors exist: mu-1, mu-2, and mu-3. The profoundly pleasurable and pain relieving properties of a mu agonist are heavily mediated through the mu-1 subtype. Activation of pre-synaptic mu-1 receptors within the lymbic area of the brain blocks the inhibitory effect of GABA, thus allowing increased cell firing of dopamine within the nucleus accumbens; this is experienced as extremely pleasurable. Mu-opioid agonists selective for the mu-1 receptor subtype allows the beneficial effects of an opioid, with lesser likelihood of the problematic respiratory depression mediated by the mu-2 subtype. Currently, no opioids are available which selectively target the mu-1 receptor type. However their development is likely to offer smarter & cleaner opioids with a superior safety and side effect profile.

Sunday, March 6, 2011

Tolerance, Dependence, Hyperalgesia & Opioid Withdrawal

A Brief overview of the two main underlying mechanisms


Down-Regulation of Mu Opioid Receptors


Mu opioid receptor down-regulation plays a key involvement in dependence. When the MOR is present in vast amounts, pain sensitivity is diminished both physiologically and emotionally, however when the MOR is present in inadequate number, an individuals sensitivity to suffering can become extreme, causing severe depression, inability to feel pleasure, and hypersensitivity to pain (hyperalgesia). As the abundance of receptors downregulates (declines), so does the natural production of endogenous opioids, most of which are critical to physical and emotional well being.

Desensitization of Mu Opioid Receptors

Mu opioid receptor desensitization produces a similar effect, however this mainly manifests through increasing tolerance to opioids. When these receptors are activated with strong agonists over periods of time, they begin to lose their sensitivity to the effects of both endogenous and exogenous opioids, requiring larger and larger amounts over time.


The Result

Together, these two mechanisms underlying dependence and tolerance complement each other; leading to a viscious cycle of increasing tolerance and abstinence syndrome. As a result of receptor downregulation and the ceased production of the bodies endogenous opioids, an individual becomes physically dependent, and now requires the constant presence of exogenous opioids (morphine, etc) in order to avoid a miserable withdrawal syndrome which can last for days or weeks. As if that's not enough; desensitization of the fewer receptors which are present requires that the individual must continuously increase the dose over time in order to provide an adequate degree of opioid activity to keep withdrawal symptoms at bay.

Saturday, March 5, 2011

Misinformation Debunked: Some Random Facts About Addiction

(1)

The disease concept of addiction originated with the temperance movement during the 19th century with a man named Dr. Benjamin Rush. Rush had speculated that those who drank alcohol excessively were 'diseased'. Dr Rush - whose deep anti-drug sentiments would eventually lead him on a passionate anti-alcohol crusade - used his disease idea to promote a prohibitionist political campaign. It is interesting to note that this very same Dr. Benjamin Rush was also convinced that dishonesty, political dissention, and being african american (i.e. 'negro-ism') were diseases as well.

The disease propaganda grew, and was endorsed by the religious cult of A.A. It was heavily pushed by a devout 12-stepper named Marty Mann and backed by a dubious scientist by the name of E.M. Jellinek, who was happy to falsify research with a group of drunks who had been handpicked by Mann (the 12 stepper). He was later asked by officials of Yale University to refute these findings which had not stood up whatsoever to actual science. The voodoo pharmacology did not stop here. As one might expect, the disease concept was eagerly capitalized upon by the American Medical Association, setting the stage for the development of a multibillion dollar annual "treatment" industry.

To this day, the disease concept of addiction has not been supported by any factual research, and remains recognized in the DSM thanks to the progressive semantic elasticity of major medical & public health organizations.

(2)

The year is 2011, and a major proportion of americans continue whole-heartedly believe that the use of any "drug"; including heroin, LSD, cocaine, even marijuana - results in imminent destruction, insanity, criminality, or death. Meanwhile - the liquor, the beer and wine, the highly caffeinated starbucks beverage, the st. johns wort, and the prozac; which they consume on a daily basis - all are either drugs or contain one or more drugs. It is perplexing to hear anyone actually debate this, and try to draw the arbitrary distinctions between "caffeine, beer, wine, etc" and "drugs".

(3)

Babies are not born addicted to drugs and are not biologically or developmentally capable of addiction to drugs. Babies whose mothers have taken narcotics such as morphine may be born with a physiological dependence to the drug and subsequently experience some physical agitation and sickness in the absence of the drug, though this is easily remedied with gradually reduced doses of the substance until they are drug free. Infants lack the cortical neuronal-connections necessary to develop an actual addiction to narcotics or anything else for that matter, and the symptoms experienced by babies are extremely mild compared to those experienced by an adult with an actual addiction to such substances. "Addicted Babies" is a phrase used by alarmist scumbags and vapid hags whose general intention is to invoke the superstitious misconception of a baby who is born doomed to the inevitability of life-long involuntary self destruction.

Wednesday, March 2, 2011

Breakthrough Pain and Breakthrough Analgesia

Since the introduction of OxyContin in the US, long acting opioid formulations have advanced along with extended release technology. Those who experience chronic pain are fortunate to have a wide variety of options for round the clock pain control; a regular schedule of a long acting opioid provides a consistent and steady baseline level of pain control.

It's important to keep in mind that 'baseline' analgesia is the key word - A patient who is stablized on a long acting opioid will remain in a similar state to a healthy individual who does not experience chronic pain, due to both constant analgesia and opioid tolerance. This suggests that any unusual sensations of pain greater in intensity than the typical everyday pain (which is controlled with a long acting analgesic) will still be experienced as bothersome to the subject. For example, lower back pain may be effectively treated symptom-wise with MS Contin every 12 hours, but the unusual pain of moving the back the wrong way worsening the symptoms or perhaps breaking a leg, will hurt just as badly as it would for anyone.

Additionally, pain levels vary day by day, for many to an incredible degree, making certain occurences of intermittent pain unforseeable for both the physician and the patient. This is where a secondary opioid should be prescribed, if necessary, for 'breakthrough' pain - breakthrough pain is the most commonly used term for intermittent sudden onset pain which the primary opioid is unable to prevent.

An ideal opioid for breakthrough pain should cater to the nature of the pain; sudden onset pain comes on quickly without warning, which requires an opioid with a similar fast onset. An ideal analgesic for breakthrough pain may generally be fast/short acting; often with long acting comes delayed onset of relief. The opioid must also be potent enough, and in large enough dose, that it provides efficient relief for a patient with already a certain degree of narcotic tolerance. Opioids such as oxycodone and morphine are often ideal for sudden onset pain, depending on the individual - Both are moderately strong and typically take no more than 20 to 30 minutes for effect, while both providing significant relief for roughly 3 hours give or take. Below is an overview of available opioids which fill the need for moderate to severe breakthrough pain; and also explain their suitability for different roles in different situations.

Hydrocodone Compounds: Hydrocodone w/ acetaminophen compounds are often prescribed for breakthrough pain along with the moderate strength long acting opioids such as morphine ER or OxyContin. This is generally an effective approach during the earlier months of treatment before a greater tolerance has developed. A more effective option in certain patients may be a hydrocodone/ibuprofen compound; often containing 7.5 to 10mg of narcotic and 200 to 400mg of NSAID. Hydrocodone compounds can be taken in doses as much as 10 to 20mg at a time, usually every 4 to 6 hours as needed, assuming that the lower-acetaminophen content medicines are used; norco, lortab, zydone, vicoprofen and reprexain are all potential canidates.




Oxycodone Compounds: Oxycodone compounds with acetaminophen or ibuprofen may suit the need for breakthrough pain as well, typically earlier on in therapy when tolerance is low - like hydrocodone compounds, oxycodon combinations contain only limited amounts of narcotic and their use is limited due to the presence of acetaminophen. The highest dose of oxycodone available in a combo form is 10mg - percocet, percodan, endocet, and combunox all suit the need for a combination product for breakthrough pain.

Fast Acting Morphine: As tolerance increases, instant release morphine offers an effective option for those who tolerate the side effects. Numerous branded and generic versions are available in both tablet and liquid forms; tablet forms generally contain 15 to 30mg morphine per tablet, and liquid forms may contain anywhere from 5mg per 5ml to the heavy concentration of 20mg per 1ml (100mg/teaspoon) - the highly concentrated product is useful in those with a compromised ability to swallow, compromised level of consciousness or with vomiting issues, because it allows small single drops to be administered easily into the mouth where they either dissolve inside or comfortably slip down into the stomach. These oral concentrates are popular with cancer or other terminal patients whom are often beyond capacity for simple functions such as swallowing. Liquid formulations also allow for a quicker absorption and onset for rapid pain relief when necessary.

Fast Acting Oxycodone: Oxycodone itself is an effective and popular opioid for those who cannot tolerate morphine due to side effects and those who simply prefer it. Oxycodone has plenty of advantages over morphine; rapid onset and excellent absorbtion by the oral route - bioavailability is much higher than morphine's. Fewer side effects in many patients than with morphine, pruritis/itching in particular is much less pronounced with oxycodone, as well as much lesser degree of sedation and lesser degree of nausea and vomiting. Unlike morphine, oxycodone often produces a stimulating state rather than sedated state - this is common in many patients and habitual users. Oxycodone is generally considered to be much more euphoric than morphine, and for some allow a greater degree of functioning each day. Studies have suggested that oxycodone may be slightly preferable to morphine in the treatment of certain types of pain, specifically visceral pain, affecting organ and soft muscle tissue. Oxycodone has been proven an effective alternative to morphine in most varieties of non-malignant pain. Like morphine, both tablet and liquid form oxycodone is available; tablets are available in a wide variety of doses of 5 to 30mg and liquids are available in as little as 5mg/5ml or the highly concentrated 20mg/1ml; which suits it for those with a low capacity for swallowing and/or stomach issues. Roxicodone is the most popular tablet form with many generics available, while liquid forms are available in a variety of branded and generic forms.


Fast Acting Hydromorphone: Hydromorphone is yet another alternative to morphine for breakthrough pain; most commonly known by the name Dilaudid, hydromorphone is a potent opioid which is very effective in relieving pain, and is well suited for patients with moderate to high tolerance. Although like morphine its bioavailability is low, in the right dose, hydromorphone may provide rapid relief from sudden pain with fewer side effects than morphine in equianalgesic doses; with 4 to 8mg of Dilaudid being similar in analgesic efficacy to 15 to 30mg of oral morphine. Tablets are the most commonly used form of hydromorphone/dilaudid, available in 2, 4, and 8 mg strengths. Brand name and generic hydromorphone is also available in liquid form, and offers rapid absorption of the drug - the standard Dilaudid oral solution contains 1mg per 1ml (5mg/teaspoon) of hydromorphone. Currently in the pharmaceutical development/research pipeline, is a rapid acting nasal spray form of hydromorphone; nasally administered hydromorphone offers a faster onset with better absorption than the oral route - Onset of oral hydromorphone may take 20 to 30 minutes, while nasally administered liquid may take effect in 5 to 15 minutes. Hydromorphone may have an additional clinical advantage to physicians, administered orally, hydromorphone is generally believed to possess lesser liability for development of misuse or compulsive use of the drug, essentially giving it a lesser tendency to precipitate a psychological dependence. This is due to the 'cleaner' effect of hydromorphone which produces less of a subjective opioid 'high' - Note, this only pertains to the oral use of the drug, and while it may offer an advantage in the eyes of physicians, many of us like to 'feel' our opioids when taken orally. Additionally, in cases of patients with already present addictive traits, this presents an incentive to take the drug by other routes such as injection or insufflation; therefore this seemingly positive attribute may serve as a downside in some situations.


Fast Acting Oxymorphone: In a similar category as the previous opioids is oxymorphone, a very potent opioid which is roughly 8 times stronger than morphine and slightly stronger than hydromorphone. Regular rapid release oxymorphone is currently available only in tablet form; the brand name Opana patent only recently expired, and subsequently 2 generic oxymorphone tablets have been introduced. Doses available are 5mg and 10mg. Though much stronger than morphine, oxymorphone has a significantly lower bioavailability than morphine, averaging only 10% in most individuals, meaning higher relative doses must be used. Milligram to milligram, oral oxymorphone has an approximate 1/2 ratio with oral morphine - 15mg oxymorphone is equianalgesic to 30mg morphine or 20mg oxycodone. This applies only to oral use, and by other routes the drug is far more potent than morphine, requiring very small doses. Oxymorphone instant release formulations are generally believed to provide a longer lived analgesia than its close relatives, and may provide significant relief for up to 5 or 6 hours. In the right dose, oxymorphone is a highly effective analgesic which provides an alternative to morphine for highly tolerant individuals or those with severe episodes of breakthrough pain. Patients who are given the drug in an adequate dose, often rate its efficacy as being among the best of the opioids. In equianalgesic doses, OM carries much less pronounced side effects than morphine, primarily the itching/pruritis, nausea & vomiting, and sedation. Many report it to be similar in subjective effect to oxycodone, though often much cleaner or smoother in effect - to many this may translate to less pronounced effects by the oral route; though this only applies to the oral route.

Buccal & Nasal Fentanyl Preparations: Fentanyl is extremely potent and is currenly the strongest opioid available in the US for outpatient management of pain; originally it was released as the 72-hour transdermal formulation after having been only used as an injectable solution in the hospital/surgical setting, however a number of rapid acting formulations have become available more recently. For breakthrough pain, the drug is currently availavle in buccal forms, which rapidly dissolve inside the mouth; on the surface of the inner cheek, gums, or tounge. The brand names for fast acting fentanyl are as follows:

Actiq - buccal fentanyl product in the form of a lolly-pop style lozenge at the end of a stick. Lolly-pop fentanyl is now available in generic forms as well; and though this product is indicated primarily for treatment of cancer related pain, it can be used off label for opioid tolerant individuals who are currently taking a potent long acting opioid such as the fentanyl patch, Opana ER, long acting morphine in high doses, or methadone.

Fentora - buccal fentanyl in the form of a fast dissolving round-tablet. Like Actiq, fentora products wre FDA approved for treatment of malignant pain, but can be used off label for non malignant pain in opioid tolerant individuals currently on potent long acting narcotics.

Newly available is a buccal fentanyl film, by the brand name Onsolis; the film rapidly dissolves on the inner surface of the cheek, gums, or tounge.

Fentanyl nasal spray is available in European countries by the brand name Instanyl, however there are currently no intranasal forms of fentanyl available in the US. It is likely in the coming years for fentanyl nasal spray to be introduced to the US market, and is reportedly being pursued currently.

Fentanyl typically recieves shining reviews from pain patients, and is generally agreed to be one of the most effective opioids for relief of severely debilitating pain, often minimally responsive to other opioids. The rapid absorbtion of instant release fentanyl is superior to most other opioids; patients often report relief within 7 or 8 minutes, often before the medication has completely dissolved. Fentanyl is perhaps one of the best suited opioids for rapid and complete pain relief, due to its fast acting properties and high potency. Analgesic effect of fentanyl usually lasts 1 to 2 hours; which makes it an idea medication in situations such as treatment with methadone or the long acting patch, as it can be used to provide fast relief during the delayed onset of the long acting opioid, with much less tendency to linger in the system once other medications have taken full effect.

Tuesday, March 1, 2011

Opioid Therapy: Chronic Pain Relief

This section was originally part of the "therapeutic uses" page, however while reformatting the blog's main pages, I've had to re-publish this section to provide it a space of its own.

Those who are ethically or ideologically opposed to the idea of long term narcotherapy for non-cancer pain often tend to cite the lack of placebo controlled long term trials or peer reviewed studies in this particular field. These individuals, whether they be doctors or laypeople, tend to emphasize this lack of definitive evidence and characterize this ambiguity itself as evidence to refute the validity of this practice. What they fail to acknowlege, perhaps out of willful density, is simple - The self-reported experience of countless individuals who will adamantly testify to the significant relief of symptoms provided by chronic use of narcotics. Such anecdotal evidence lacks the empirical objectivity to which one could apply a standardized means of measurement. These patient reported benefits include cognitive and emotional improvement, restored sense of passion for life, improvement in function, increased social & economic productivity, restoration of physical energy, improvement in interpersonal relationships and a reduced degree of suffering overall.

Criteria for Opioid Therapy: Palliative opioid therapy as a pain treatment, is generally most likely to be considered by Doctors under the following conditions.

a) Has been present for weeks, months, or years, lasting at least 12 hours per day at an intensity of at least 5 on a10-point pain scale.

b) Interferes with sleep, self grooming or hygeine, independence, employment, and other tasks deemed essential to a productive lifestyle.

c) Exacerbates an unrelated condition such as heart disease, severe depression, etc; or interferes with the course of treatment for such an underlying condition.

d) Has resulted in a marked deterioration of physical or emotional health.

e) Some of the more gracious Doctors will consider a deterioration in quality of life itself as sufficient indication for chronic opioids, assuming one is currently capable of giving informed consent.

The Case for Opioid Therapy

Narcotics are not given to "cure" pain or to "fix" the source of pain. They are not effective in doing either - but this by no means negates their value. The phenomena of pain is more complex than some would have us believe. To debate the merits of narcotics for pain is not as simple as debating whether they treat the source or mask the symptoms. Ignorant opponents of chronic opioid use maintain the misconception that opioids merely cloud the perception of pain, and claim that pain is merely a symptom which in itself does not merit a potentially 'habit forming' treatment. This is a mistruth. Pain in its simplest and acute sense is indeed a symptom - often secondary to an injury or illness - and even so, for pain as a symptom to be denied treatment, especially over irrational fears of 'addiction', is pointless, idiotic and inhumane. The simplistic view that "pain is pain is pain", is especially senseless. It must be established that pain occurs in many different forms under many different circumstances. Pain is a complex biological state, of which our understanding is still in its infancy, and manifests as far more than just a symptom. Pain can range from a symptom, to a condition, to a chronic disorder in itself. When chronic pain is considered by its clinical definition, the implication that chronic pain is merely a symptom is completely false.

Chronic pain (or CP) is a state of disorder typically involving the central nervous system. The very fact that CP is often a "symptom of nothing", is the basis for its classification by some as a medical 'disorder'. In the case of chronic pain, what once may have been a symptom has remained long past healing time of the original injury or illness. 

Chronic pain targets the pain pathways within the dorsal horn of the spinal cord. What often begins as symptomatic pain may develop into chronic pain over time if the pain itself is not well controlled. The untreated pain with time leads to neuroplastic changes involving ascending C-fiber pathways and descending modulatory pain feedback pathways - a process known as long term potentiaton. In effect - Pain pathways within the spinal cord continue transmitting pain in the absence of any actual damage or inflammation.

Given for acute pain, opioids change the perception of pain, inhibit the reaction to pain, and calm the pain transmission (i.e. nociception) itself at the spinal level - this prevents the aforementioned adaptive changes in which lead to chronic pain. When symptomatic pain is left untreated to become chronic, this is where pain becomes much more complicated to manage and to treat.

In any discussion of acute or chronic pain, one must acknowledge the naturally occurring painkillers of the body - the endogenous opioids (i.e. endorphins). "Endorphin" is often used as a broad term to cover a spectrum of naturally occurring neurotransmitters in the body, which act in the same way & at the same receptors as narcotic drugs like morphine and heroin - i.e. binding to opioid receptors and inhibiting the transmission of pain from one neuron to the next. Endorphins are released into the bloodstream and spinal fluid, and naturally relieve pain and distress during injury, illness, or stressful experience. 

Opioid drugs (i.e. narcotics) are known as exogenous opioids, as their source is outside of the body. During symptomatic pain, narcotics are given when the pain is too great for endorphins to manage. During chronic pain, endorphins are produced and released, but the pain has long since exceeded the point of responding to endorphins. Furthermore, as discussed prior, chronic pain becomes a full blown dysfunction, without a source which can be repaired or healed. The only possible treatments will target the central nervous system - i.e. the pain pathways of the spinal cord, the physical response to pain by the brain, and the perception of pain by the brain. The opioids target all three elements.

To clarify further; research is still in its infancy in regards to fully characterizing the mechanisms underlying the deep rooted neurobiological changes present in chronic pain. However, opioids do in fact attack the pathological product of such changes, by countering the transmission of such seeming source-less nociceptive stimulus. In the process of doing so, the narcotics are effective in treating the many problematic physiological, psychological, emotional & behavioral impacts of chronic pain (which will be covered in more detail below).

Purposes of Opioid Therapy for Chronic Pain:

First and foremost; to reduce the flow of pain transmission to the brain and calm the physiological reaction to pain.

To increase one's tolerance to pain and to alter the perception of pain and reduce its negative impact on emotions. Opioids cause euphoria or have a positive effect on mood in many individuals. Some pain may be present, but will be much less bothersome.

Prevent the complications of long term pain on physical health. Untreated pain may cause or worsen high blood pressure, other cardiovascular conditions, interfere with vital functions such as rest, sleep, and food intake, lead to major weight changes, reduce physical energy, and in some cases lead to heart attack, stroke, and death.

Prevent the complications of pain on mental health - as untreated pain may directly or indirectly lead to anxiety or depressive disorders, complicate underlying mental illness, impair cognitive function and social skills, and in some cases lead to nervous breakdown or suicide.

Restore and maintain an adequate state of physical and psychological function.

Increasing function!! Opioids will lead to increased mobility, better function, employability and financial productivity, energy, hygeine, excersize and independence.

Quality of life!! Improvement in mood, motivation, and a restored interest in personal passions, thus allowing a better quality of life.

An ideal approach to chronic opioid therapy may also include the following:

Regular visits to assess and re-assess the efficacy and response to opioids, to review the patient's med use and med reactions, and to make any changes needed. A good doctor will counsel the patient adequately regarding the major points of narcotic therapy - physical dependence, tolerance, proper use, serious side effects, and other limitations.

Quality documentation of pain patterns and responses to treatment. Keeping a pain journal or diary, and periodic assesment of pain on a graded scale - this over time will allow a doctor to become more familiarized with an individuals personal pain scale, and to analyze progress and assess future goals.
Physical therapy when necessary to promote fitness and use of the body and maintain further function, mobility, and independence.

Adjuvant analgesics or analgesic techniques; i.e. gabapentin, pregabalin, SRI's or NRI's; steroid injections; local anaesthetics or nerve blocks; NMDA antagonists to slow tolerance + enhance analgesia; icing, wrapping, massage, or heating techniques; acupuncture.

Psychosocial therapy never hurts; even for those in perfect health. Periodic individual or group type counseling helps many people to remain socially engaged, in tune with others, and may promote or maintain a healthy relationship with their opioid medications (and family or friends). Talking with others is generally beneficial for most individuals, in one way or another.

Regular primary care to address physical health as a whole and to treat any unrelated underlying conditions such as heart disease, obesity, diabetes, asthma, etc. This may include monitoring of testosterone levels, enzyme levels, neuroendocrine function, digestive function, and reproductive function - such functions specifically might require attention to address the common opioid side effects, which can easily by treated/managed.

Diet and lifestyle changes, emphasis on nutrition, excersize, sleep habits. Emphasize the importance of a healthy lifestyle and nutritional balance; incorporate this into any treatment plan.

Any ongoing (or necessary) psychiatric care - including initiation or maintenance of any current psych meds for underlying mood disorders such as OCD, ADHD, major depressive or anxiety disorders, sleep disorders, etc.

What to expect with chronic opioid therapy:

Initiation of chronic narcotic therapy is often referred to by doctors as an opioid trial. The trial phase will likely involve induction with a short acting narcotic, usually morphine, given in a modest dose every 4 hour; this will be supplemented with additional rescue doses, which are taken intermittently "as needed". 

Rescue doses may be taken as often as needed, as frequently as every hour - keep in mind this is the trial phase. The dose is assessed each day or two and pain relief is assessed. Once a consistent level of relief is observed at a given dose (with pain measured on a 10 point scale) the total daily dose, including the rescue doses which were required, is established. This process of "low base dose + rescue dosing" allows both doctor and patient to establish the lowest effective dose without guessing and "shooting high". In some cases, a number on the pain scale would already have been selected beforehand to represent the pain-relief goal; determined by the level of pain which the patient believes would be manageable. 

The proper level will be the dose which gives the most effective relief while producing the fewest adverse effects; generally sedation and somnolence. 

Once the proper dose is established, the total daily dose is given as either an ER or IR formulation of the same opioid, or converted to a new opioid in an equianalgesic dose. Whether a long or short acting medication is used will depend upon the nature of the pain.

Relieving Chronic-Consistent Pain:

If the drug is being considered for chronic-consistent pain which is present throughout most if not all of the day, it is standard practice to use a long acting opioid - this may be a traditional semi-synthetic opiate in a contolled release form, or it may be a regular non modified form of a naturally longer acting opioid. The typical first choice of most doctors is morphine as an extended release formulation such as MS Contin, Kadian, Avinza, or Embeda, (the latter of which contains an inactive opiate antagonist to prevent misuse of the pill) - MSContin is designed to last 8 to 12 hours, Kadian lasts 12 or more hours, Avinza lasts 24 hours, and Embeda lasts 24 hours. If morphine is inadequate or inappropriate due to poor pain relief, adverse effects, or hypersensitivity/allergy, the common second options are 12-hour oxycodone (OxyContin), 12-hour oxymorphone (Opana ER), or a transdermal fentanyl patch which is applied every 2-3 days. One possibility is a newer once daily hydromorphone tablet called Exalgo, but like every narcotic pain medication introduced after 2010, doctors must jump through some bureaucratic hoops to become registered to prescribe it; which leaves the two third tier options. Methadone and levorphanol. Both are available as generics. Methadone is the cheapest opioid available price-wise, and is taken a few times daily. Individuals vary in their reactions to methadone, so selecting a dosing interval is trial and error. Levorphanol is available as a generic from only one manufacturer, and is more costly than methadone. It is generally taken at an interval of anywhere from every 6 to 12 hours.

Long acting morphine: A common initial dose for MS Contin is 15 to 30mg every 8-12 hours for an opiate naiive individual. Certain products such as avinza can be taken once daily at doses up to around 60mg. Individuals requiring more than 60mg morphine daily are clinically considered opiate tolerant.

OxyContin is the only long acting oxycodone available. In those who are not switching from morphine or another opioid, it's given in doses of 10-20mg every 8-12 hours, depending on how quickly it wears off in a given individual. Individuals requiring more than 30-45mg of oxycodone per day are clinically considered opioid tolerant.

Oxymorphone ER is generally given only to opioid tolerant individuals. A typical starting dose is dependent upon their previous dose of a given opioid. For a patient who had previously taken 60mg morphine, or 40mg oxycodone, twice daily, Opana ER would ideally be started at 20-30mg every 12 hours.

The transdermal fentanyl patch is reserved for opioid tolerant individuals - even the 25ug/hour patch is reserved for those taking well over 100mg morphine around the clock. A dosing chart is included below. Note that according to medical standards: "Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer."

Methadone dosing is typically trial and error. Potency is inconsistent between individuals, but as doses increase, its morphine relative potency multiplies - in other words, it has a non linear, upward curve in dose-effect. Most doctors are cautious, starting with 2.5 to 5mg every 8 to 12 hours, taken as needed during induction. Once a steady dose is acheived, methadone is given every 6 or 8 hours around the clock. However, intervals up to 12 hours are sometimes appropriate in the elderly, who often exhibit lower hepatic and renal clearance. In any case, methadone lingers in soft muscle tissues and plasma - to the extent that blood levels in those maintained on the drug may reach several times those seen with a single dose - therefore, doses may be tapered down significantly once one is stabilized on methadone.

Levorphanol is reccomended primarily for tolerant individuals, however this is not always the case. A typical starting dose is 2mg every 6 to 8 hours, given around the clock in cases of consistent CP. Higher doses may be given in tolerant individuals; every 4mg of oral levorphanol is comparable to 30mg oral morphine, and intervals are generally the same. In any case, levorphanol lingers in plasma - to the extent that blood levels in those maintained on the drug may reach 5x those seen with a single dose - therefore, doses are often tapered down significantly once one is stabilized on levorphanol.

Once daily hydromorphone (i.e. Exalgo) may be used by doctors who have acquired the proper registration, however the doses available in the US are unreasonably low for almost any opioid tolerant individual, the highest dose tablet available contains 16mg. Individuals taking this product may require multiple tablets per day. An alternate approach would involve the addition of a second opioid with an incomplete cross tolerance to hydromorphone, to create drug synergy & a subsequent sparing effect.

Buprenorphine has been around for ages, yet its use in the US for chronic pain is fairly new - a 7 day transdermal skin patch is the only american buprenorphine medication approved for pain at this time. BuTrans is applied to the skin like the fentanyl patch, and is changed every 5 to 7 days. Buprenorphine is over 30x more potent than morphine, and 1/3 as potent as fentanyl and is used in microgram doses ranging from 5 to 20ug per hour in the case of BuTrans. In this dose range, buprenorphine produces typical morphine-like effects, with an agonist dose response curve which does not exhibit a plateau in response. Also owing to its agonist properties in low doses, buprenorphine can be supplemented with opioid agonists such as morphine, oxycodone, hydromorphone, etc.

Relieving Chronic-Intermittent Pain:

There is an entirely different approach to medicating chronic cases of intermittent pain. Such cases can include chronic renal colic (i.e. recurring kidney stones), migraine attacks, cluster headaches, and severe tension headaces. In this case, a short acting opioid is usually given to be taken as needed. This may amount to the occasional 'here and there', or at certain times each day as a result of certain physical activities, or as frequently as several times each day. A short acting opioid for this purpose is ideally equally quick to take effect. Pain relief is always best when medications are taken right away, at the first sign of pain, or before a certain activity in anticipation of pain.

Doctors may start off providing compounded meds such as hydrocodone w/ acetaminophen (Vicodin, Norco, Lortab) or oxycodone w/ acetaminophen or aspirin (Percocet, Percodan, Endocet). Either way, there will likely reach a point that drug tolerance has increased to where one is taking up to 12 tablets daily, the maximum number recommended as acetaminophen is toxic in higher doses. At this point, traditional single entity narcotics are given. Morphine and oxycodone are the most popular in the US. Hydromorphone (i.e. Dilaudid) may be a first choice when particularly rapid relief is desired. Oxymorphone immediate release in the form of Opana IR is comparable to morphine & oxycodone in its onset, peak, and duration, and is used as another alternative to morphine. Opana is twice as potent as oxycodone by milligram when swallowed.

Norco, Vicodin, Lortab (hydrocodone compounds): common dosing is 5-10mg every 3 to 4 hours, or 10-20mg every 4 to 6 hours. No more than 4,000 mg acetaminophen in 24 hours. Up to 120mg of hydrocodone can be taken per day. This translates to 12 Norco tablets containing 10mg hydrocodone w/ 325mg acetaminophen.

Percocet, Endocet (oxycodone compounds): common dose is 5-10mg every 3 to 4 hours, or 10-20mg every 4-6 hours. 120mg of oxycodone can be taken per day before exceeding the ceiling for acetaminophen - this is equal to 12 percocet tablets containing 10mg oxycodone w/ 325mg acetaminophen.

Morphine oral: Common starting dose is usually 15 to 30mg every 3 to 6 hours. There is no limit on dosing for tolerant individuals. Chronic users may reach daily doses of several hundred milligrams to several grams per day.

Oxycodone oral: Common dose is initially 10-15mg every 3 to 6 hours, which can be increased to 30mg if required. No dose limit for tolerant individuals.

Hydromorphone oral: Common dose is usually 2-4mg every 3-4 hours, which can be increased to 8mg if needed. No dose limit with dilaudid.

Oxymorphone oral: A common starting point is 10-20mg every 4-6 hours. With its low oral bioavailability, this is equivalent to 1-2mg by injection every few hours.

Some key points to keep in mind:

Dosing at regular intervals (around-the-clock) is preferable to dosing as needed. With chronic treatment, analgesics are almost always most effective when the analgesic is given preventatively, meaning before pain develops.

If pain is infrequent or intermittent however, chronic migraine or tension headache for instance - analgesics should be taken immediately at the very first indication of oncoming pain.

When taking an opioid for around the clock pain control (i.e. baseline analgesia), many doctors will supply a supplemental narcotic for sudden onset flares of pain, known as 'breakthrough' or 'rescue' medication. Ideally this will be a rapid acting and perhaps short acting narcotic, which is suited for quick relief of sudden onset pain. Popular narcotics for this purpose (in the US) are oral oxycodone, oral hydromorphone, oral oxymorphone, oral hydrocodone with acetaminophen, and sometimes buccal or sublingual fentanyl. Given elsewhere around the world for this purpose may also be oral or injectable morphine or diamorphine, injectable buprenorphine, dipipanone, dextromoramide, and nicomorphine.

Your doctor may be empathetic and compassionate, and may be happy to help you manage your pain. Your doctor may be a family physician you've seen for years. But the fact remains that the majority of doctors fear police investigation, prosecution, and career ending sanctions. Those taking opioids for true chronic pain who are fortunate enough to have access through a good doctor, should always take care to avoid ruining a great situation. Doctors are hyper-vigilant for what they refer to as abbarrent drug related behaviors - Avoid dropping red flags. Just use some common sense.