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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").

Thursday, December 9, 2010

Atypical Analgesics

Tapentadol:

Basic

Tapentadol is a centrally acting analgesic with a dual mode of action as a norepinephrine reuptake inhibitor (NRI) and a selective mu-opioid agonist. The dual mode of action distinguishes it from other opioids. Tapentadol is very young to the US market as it was released within the past 3 years.

Use

Nucynta: 75mg Tablets (Tapentadol HCL)
Tapentadol (brand name Nucynta) is used to treat moderate to severe acute pain. Currently the drug is solely available in the short acting form, which suit it for acute or short term pain. Its dual mode of action suits it for atypical types of pain which may show little or no response to conventional analgesics such as typical narcotics or NSAID's/APAP. Nucynta is most often useful for acute, irregular pain such sprains, fractures, lacerations, burns, toothache, headache or postoperative pain. It may also be used (as it increasingly is) in chronic pain therapy as a supplemental analgesic for episodes of sudden onset or breakthrough pain - typically in patients being treated with a traditional long acting narcotic such as morphine, oxycodone, or transdermal fentanyl. In a marketing and clinical sense; It plays a role similar to that of Dilaudid, if merely in the sense that its rapid acting/short-lived properties lend an 'acute or breakthrough' treatment appeal to the drug.

Based on clinical evidence and literature, it is suggested that tapentadol in the dose range of 50 to 100mg produces analgesia comparable to that of a 7.5 to 15mg dose range of oxycodone IR.

Tapentadol is currently under patent and as such is available only as the original brand name product, Nucynta - the name being derived from "New", and "Synthetic" - as it is the first centrally acting analgesic (not to mention opioid) to be marketed in the US within the last 25 years. Nucynta is currently available as tablets for oral use, in doses of 50, 75, and 100 milligrams.

Properties

Chemically, tapentadol is a novel analgesic acting as a functional analogue to a major metabolite of tramadol. Technically, atypical analgesics such as tapentadol (or tramadol) show superior potential in treating a spectrum of depressive-anxiety or personality disorders; due to a dual mode of action - i.e. monoaminergic agent (SRI, NRI) and opioid agonist. The latter offers a profound boost in efficacy - especially appealling to the mainstream when combined with the serotonin/norepinephrine properties. Tapentadol is pharmacologically similar to tramadol and o-desmethyltramadol ("M-1"), but has a greater affinity & efficacy at mu-opioid receptors, and a correspondingly greater dependence-tolerance liability.

Tapentadol is 18x less potent than morphine as a mu agonist. Tapentadol is 2-3x less potent as an analgesic according to animal-studies. This is supportive of its multiple modes of action (NRI + mu-agonist)

Molecular Structures of tapentadol


Tapentadol is centrally active in itself - pharmacological effects of the drug are produced by tapentadol rather than a metabolite. Tapentadol was created as a structural/functional analogue of tramadol's major active metabolite o-desmethyltramadol and was succesful in emulating these pharmacological properties. Tapentadol shows a high affinity and selectivity to the mu-opioid receptor, with a clinically negligible affinity for kappa & delta receptor. Additionally, the drug acts as an inhibitor of norepinephrine reuptake (NRI) as well as a modest inhibitor of serotonin reuptake (SRI) - Studies showed tapentadol to produce dose dependent increases in extracellular norepinephrine levels up to 4x greater than baseline, with serotonin levels showing a modest dose-wise increase of up to 30% higher than baseline. This second mode of action as an (S)NRI compensates the relatively mild mu-opioid properties by creating a pharmacological synergy which produces greater analgesia than either mode of action alone.

Bioavailability after oral administration is approximately 32% owing to extensive first pass metabolism. The drug has a half life of approximately 4 hours. Excretion/elimination of tapentadol is almost completely via the kidneys (renal).

Effects 

According to an abuse liability study sponsored by the manufacturer, the minimum available dose of 50mg tapentadol produced subjectively similar opioid effects (euphoria, anxiolysis) to that of 4mg of oral administered hydromorphone. The study went further to suggest that tapentadol in doses of 100mg and 200mg produced similar subjective narcotic effects to hydromorphone doses of 8mg and 16mg respectively.

Those who have used the drug therapeutically or recreationally have reported common side effects; including the usual spectrum of opioid side effects (itching, miosis, emesis, respiratory depression) in addition to stimulant type side effects (hypertension, restlessness, jittering, anxiety, tension, insomnia)

Tapentadol in opioid tolerant individuals may not produce significant narcosis at therapeutic doses, however those who have attempted higher doses (400-600mg) describe effects as quite pleasant, similar in nature to oxycodone; i.e. euphoria, anxiolysis, positive mood.


Tramadol:


Basic

Tramadol is a bicyclic (2-ring) synthetic analogue of codeine
Tramadol is a synthetic non opium based compound created as a structural analogue of codeine with multimodal activity (note the similarity in structure on the left). The drug is available for oral use as a single entity product by the brand name Ultram; as a compound with acetaminophen by the brand name Ultracet; or as a solution for parenteral use. Tramadol as a branded drug is marketed by its creator Grunenthal, a german pharmaceutical firm.

Tramadol is a centrally acting analgesic with opioid and non opioid activity; used in the US and elsewhere for the treatment of moderate to moderately severe acute or chronic pain.

Tramadol is pharmacologically related to tapentadol, i.e. Nucynta. And structurally related to the popular antidepressant drug venlafaxine, known by its brand name Effexor, or the newer stereospecific product, Pristiq.

Use

Despite only mild opioid action, tramadol is effective as an analgesic, and is reported to be euphoric by some opiate naive users. Its use in medicine is relief of mild to moderately severe pain. If tramadol is the only option available, it might very well be effective in cases of severe pain, most likely in those not already taking narcotics for pain. Tramadol is usually given for acute pain such as that associated with urgent care or ER visits. Ultram is often given by doctors to suspected "drug-seekers" in either of the aforementioned settings. It may be used for dental pain such as a simple toothache, or after minor procedures such as fillings, root canal, or tooth removal. Tramadol is a good choice for burn or laceration pain, and for the pain of a severe tension headache or migraine. Tramadol has been given long term for fibromyalgia, diabetic neuropathy, and other cases of neurological pain, usually taken 'as needed' - for pain flare-ups. A long acting tablet form of tramadol is currently available as Ultram ER, offering analgesia aound the clock.

Tramadol has been used off label to treat symptoms of major depressive or anxiety disorders, usually after various tireless courses of the more toxic but morally acceptable tricyclics, SSRI's & SNRI's, MAOI's, benzodiazepines and perhaps amphetamines have failed. Its particular efficacy for depression and anxiety derives from the addition of opioid activity as a complement to the serotonin-norepinephrine enhancing properties. The opioid component provides unquestionable efficacy as an antidepressant, with a lesser level of dependence than a full agonist, even codeine. The opioid component also provides greater anxiolysis than an SSRI without the cognitive or psychomotor impairment seen with long term benzodiazepine use, and may smooth out some dirty or lethargic side effects of the monoaminergic activity.

Pharmacology

Tramadol is a racemic compound composed of a (1R, 2R) enantiomer and a (1S, 2S) enantiomer. The (R) enantiomer is responsible for the opioid and serotonergic effects while the (S) enantiomer is responsible for the noradrenergic effects.

Tramadol has a dual mode of action acting as a weak opioid agonist and a serotonin-norepinephrine reuptake inhibitor. The drug is highly selective at the mu opioid receptor but with a weak efficacy - meaning it produces a weak agonist effect. Some literature classifies tramadol as a partial opioid agonist. Though the parent drug itself contributes to the SNRI effects of the drug, tramadol relies on its more potent O-demethylated metabolite, O-desmethyltramadol (or M1), for most of its mu opioid analgesic activity. M1 is believed to be 6x more potent of an analgesic than tramadol, with roughly 200x tramadol's affinity for the mu receptor, and additional activity at the norepinephrine transporter. To summarize its pharmacodynamic profile; The SRI efficacy is produced by tramadol itself; while the NRI activity is produced by both tramadol and O-desmethyltramadol.

The multimodal action of tramadol and similar drugs derives its efficacy from the synergistic action between the opioid system and the serotonergic and noradrenergic systems. While mu receptors stem the flow of pain to the brain and changes the experience of pain; serotonin and to some extent norepinephrine modulate spinal pain modulation pathways which run from the brain to the dorsal horn; stimulating the endogenous opioid system and further stemming pain flow to the brain. Tramadol induced analgesia is only partially antagonized by naloxone, supporting the notion that the SNRI actions contribute to its efficacy. Current research continues to identify previously unknown connections between the serotonergic/noradrenergic and the opioid system. This could raise many more questions pertaining to a role of the opioid systems in modulation of anxiety or depressive disorders.

Tramadol is well absorbed orally with a bioavailability of 75%. Tramadol is metabolized by the liver, undergoing N and O-demethylation, sulfation, and glucuronidation. O-demethylation carried out by CYP2D6 forms its active M1 metabolite - making it susceptible to drug interactions or a lack of response in those who lack the 2D6 enzyme (i.e. about 7% of the population). Those who are non responsive to codeine may be non responsive to tramadol. Tramadol is additionally a substrate of CYP3A4. The parent drug and its metabolites undergo second phase conjugation, and are excreted renally - i.e. mainly through the urine.

Tramadol begins to produce effects one hour after dosing, which reach a peak at 2 to 3 hours. Tramadol itself has an elimination half life of 6.3 hours, M1 has a half life of 7.4 hours. As such, tramadol is longer acting than codeine, hydrocodone, and other opiates, with efects which may last up to 8 hours. Tramadol is typically given every 4 to 6 hours when prescribed for pain. Steady state blood levels are generally reached within 2 days with regular dosing (every 6 hours).

Effects

Being a mild opioid, tramadol produces some subjective effects and side effects that are similar to opioids such as codeine. Although these effects may be less pronounced, or unattainable in the opioid tolerant individual.

Subjective effects may include analgesia, anxiolysis, wakefulness or trouble sleeping, a sense of motivation, relaxation, a sense of well being and a positive effect on mood. Tramadol is much less sedating than typical opioids, due to its effects on norepinephrine (i.e. noradrenaline).

Side effects may include miosis, constipation, nausea and vomiting, respiratory depression, myoclonus, headache, ear ringing, orthostatic hypotension, sweating, and hot flashes. Little or no significant histamine release has been observerved in studies, though itching has been reported by individuals. As with any opioid, tramadol can cause respiratory depression which can be harmful or fatal, though this is rare with tramadol, and occurs mainly in naive individuals with excessive doses. One hazard which sets tramadol apart from other opioids is the very real risk of serotonin syndrome and grand mal seizure - Doses in excess of 400mg in 24 hours is likely to provoke seizures and in severe cases death.

Etonitazene: 

Synethetic opioid analgesic with prototype morphine like effects. Etonitazene is not used medically but is used in research on the opioid receptors.

Etonitazene is a benzomidazole compound, molecularly distinct from other opioids. It is closely related to the opioid clonitazene; both are derived from the parent compound nitazene.

Etonitazene is an ethoxy derivative of nitazene while the latter is a chlorine derivative. The related compound clonitazene is roughly 3x as potent as morphine, while the parent compouns is 2x as potent as morphine.

Its potency is similar to fentanyl as an analgesic in humans, but may be at least 10 or 15x greater than fentanyl in animals. Acts predominantly at the mu receptor as an agonist with high efficacy and affinity.

Has been manufactured clandestinely and sold as a heroin alternative. Due in part to its unique structure and therefore ambiguous legal status; as well as the relative ease in obtaining the precursors. It was identified on the illicit market in Moscow in 1998.

Administered by intranasal, parenteral and possibly oral routes. Has been smoked, snorted and injected by casual users.

Tilidine:

Racemic Tilidine
Tilidine is a synthetic opioid. It is used in some countries, excluding the US, as an analgesic for moderate pain and for the treatment of restless legs. The drug is available itself under the trade names Tilidin and Valoron, or as a combination of tilidine with naloxone, under the brand name Valoron N.

Tilidine is a mild to moderately strong analgesic. It can be taken by the oral, rectal, or parenteral routes, but is most often used orally. The typical dose is 50-100mg, which is equianalgesic to around 10-20mg of oral morphine. The effects of this drug are due mainly to its N-demethylated metabolites nortilidine and bisnortilidine.

Tilidine has an atypical structure, different from most commonly referenced opioids. Chemically it can be considered a substituted arylcyclohexylamine (or more specifically, phenylcyclohexenamine) - its closest relative of the opioid family being tramadol.

4 comments:

  1. 'tapentadol is a member of the cyclohexanol family'

    Really? I mean, REALLY? There is no cyclohexanol or even a vestige of a cyclohexanol. It was discovered by the same team as tramadol but I can find no literature describing it as you do. It's an open-chain mono-aryl opioid (like tramadol). There may be a preferred term, but not cyclohexanol... please!

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  2. Hey, thanks for the correction. I'll admit that I have never been well versed in chemistry, and pretty much try to pick up the basics as I go along; Definitely don't want innacurate info up here, so thanks for the input!

    Consider that fixed.

    MWL

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  3. Tapentadol was useless when given to my mom who has serious degeneration of her bones including a colasped s-shaped spinal column, and will be life ending. She is given Duragesic patch of 100 ug/hr and 30 mg og Morphine for breakthrough pain. Morphines poor bioavailability had the doctor place her on Tapentadol 100 mg QID. It had no effect and with proof that the best oral opiate is Oxycodone, she is taking 20 mg Oxycodone IR for breakthrough pain. So her pain is controlled with 100 ug/hr of Duragesic and 20 mg Oxycodone IR QID.
    Since I have Fibromyalgia I asked if I could try her Nucynta and this would be the only pain medication that completely stopped the trigger point pain and has no CNS drowsiness.

    I will look and one day find a Doctor who will prescribe Nucynta for my Fibormyalgia and myofascial pain syndrome. For now Mom agreed not to throw away the 3 months of Nucynta 100 mg.

    As for being a Schedule II, the DEA went too far and I hope when mixed with tylenol or another drug, Nucynta will be Schedule III.

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    Replies
    1. Thank you for your comment, very good input. I'm so sorry to hear about your mother. I can't imagine how that level of spinal degeneration would affect someone. If your mother has a history with more potent opioids then I would've been surprised if tapentadol DID do anything for her.. Although I suppose its mode of action is somewhat unique from morphine, in that it may enhance ascending pain modulatory pathways to a greater extent than typical opioids. I'm glad to hear it worked for you. Alot of conflicting anecdotes on tapentadol's efficacy - it seems to work great for some, and terribly for others. I do think the CII status was overkill - but in this day and age, I would bet anything that even if tramadol were reintroduced (as a brand new compound), it would be given a CII classification. It's terrible, I'd like to see our current system of controlled substance laws removed completely; to include prescription laws.

      Rarely can you go wrong with oral oxycodone - very versatile drug. My grandmother has taken it for years and for her it seems to provide a decent degree of relief with a minimal degree of adverse effects.

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