Methadone

Methadone is the marathon runner of the opioid family -- measured, steady, built for endurance rather than spectacle. Its onset is unhurried, taking anywhere from one to three hours to fully manifest, a glacial pace that tests the patience of anyone accustomed to faster-acting compounds. The first signs are subtle: a faint easing of tension, a warmth so diffuse it could almost be attributed to the room temperature. There is no rush, no wave, no moment of dramatic arrival. Methadone simply accumulates, building its effects in imperceptible increments until, at some point, you realize the world has quietly changed.

The peak, when it finally consolidates, is characterized by a broad, flat warmth that lacks the soaring highs of hydromorphone or the cozy intimacy of hydrocodone. The comfort is genuine but restrained, more functional than recreational -- a warmth that stabilizes rather than intoxicates. Pain relief is thorough and reliable. The body relaxes into a steady state of ease that feels less like pleasure and more like the absence of suffering, a distinction that matters enormously to those who have experienced both. There is a mild euphoria, but it wears a business suit; it is professional, competent, and entirely lacking in the giddy excess of its shorter-acting relatives.

Physically, methadone produces a moderate warmth that distributes itself evenly throughout the body. Pupils constrict. Breathing slows, but gradually and predictably, without the sudden respiratory depression that characterizes more potent compounds. The drowsiness is present but manageable, a gentle pull toward rest that can be overridden with effort. Sweating is common, sometimes profuse -- a distinctive feature that distinguishes methadone's physical signature from other opioids. The itch is mild or absent. Constipation is pronounced and persistent, often more troublesome than with shorter-acting compounds simply because the effects last so long.

The defining characteristic of methadone is its duration. The plateau stretches for twenty-four hours or more, a vast, flat plain of steady comfort that eliminates the peaks and valleys of shorter-acting opioids. This steadiness has a psychological dimension: there is no clock-watching, no anxious calculation of when the next dose is needed. The warmth simply persists, hour after hour, a reliable presence that becomes almost invisible in its consistency. By the end of the first day, you may forget you are under the influence of anything at all.

The offset is as gradual as the onset. The warmth thins over the course of a full day, so slowly that the transition back to baseline is almost imperceptible. There is no crash, no sudden vacancy. The body adjusts without protest, easing back into its unmedicated state with a smoothness that belies the compound's considerable pharmacological potency.

Opioids exert their effects by binding to and activating the μ-opioid receptor. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement. The bioavailability of orally administered methadone can vary from 40% to around 99%. Methadone is metabolized by the cytochrome P450 system.

Unlike most opioids, methadone is a weak serotonin reuptake inhibitor as well as a weak NMDA antagonist. Similarly to dextropropoxyphene, methadone is a nicotinic acetylcholine receptor antagonist.

The metabolic half life of methadone differs from its duration of action. The metabolic half life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half life of 1 to 5 hours for morphine. The length of the half life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.

Levomethadone (the L enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity. Dextromethadone (the S enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain.

Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.

• Binding affinities (Ki)

Dextromethadone:

• Mu opioid agonist - 24.8 nM
• Kappa opioid agonist - 543 nM
• Delta opioid agonist - 1674 nM

According to a study published in the Journal of Pharmacology and Experimental Therapeutics, the dissociation constants (Kd) of Levomethadone at the different opioid receptors are as follows:

• Mu opioid agonist - 2.5 nM
• Kappa opioid agonist - 54 nM
• Delta opioid agonist - 97nM

moderate toxicity relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also lethal when mixed with depressants like alcohol or benzodiazepines]] and generally has a wider range of substances which it is dangerous to combine with in comparison to other opioids. Methadone is known to lower the seizure threshold. It should not be taken during benzodiazepine withdrawals as this can potentially cause seizures.

It is strongly recommended that one use harm reduction practices when using this drug.

As with other opioids,extremely addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that,3 - 71 - 2 weeks to be back at baseline (in the absence of further consumption). Methadone presents cross-tolerance with Cross-all other opioids, meaning that after the consumption of methadone all opioids will have a reduced effect.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance. To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.

• Psychedelics** - Methadone is known to lower the seizure threshold and psychedelics may act as triggers for seizures in those who are susceptible to them.
• Serotonin syndrome risk

While methadone has been reported to occasionally cause serotonin syndrome when combined with certain substances (such as those listed below), anecdotal reports suggests that it does so at a much lower rate than tramadol.

• Canada:** Methadone is a Schedule I Controlled Substance.

• Germany:** Methadone is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.

• Russia:** Methadone is a Schedule I controlled substance.

• Switzerland: Methadone is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.

• United Kingdom:** Methadone is a Class A, Schedule 2 drug in the United Kingdom.

• United States:** Methadone is a Schedule II Controlled Substance.

• Responsible use

• Opioid

• Tramadol

• Fentanyl

• Dextropropoxyphene

• Methadone (Wikipedia)

• Methadone (Erowid Vault)

• Methadone (Isomer Design)

• Methadone (DrugBank)

• Methadone (Drugs.com)

• Methadone (Drugs-Forum)

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium and morphine shortage problem. On 11 September 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had little relation to morphine or other "true opiates" such as diamorphine (Heroin), desomorphine (Permonid), nicomorphine (Vilan), codeine, dihydrocodeine, oxymorphone (Opana), hydromorphone (Dilaudid), oxycodone (OxyContin), hydrocodone (Dicodid), and other closely related opium alkaloid derivatives and analogues. It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.

In the 1930s, pethidine (meperidine) went into production in Germany; however, the production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research. After the war, all German patents, trade names, and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US. The report published by the committee noted that while methadone itself was potentially addictive, it produced "considerably" less euphoria, sedation, and respiratory depression than morphine at equianalgesic doses and was thus interesting as a commercial drug. The same report also compared methadone to pethidine. German researchers reported that methadone was capable of producing strong morphine-like physical dependence, which is characterized by opioid withdrawal symptoms which are lesser in severity and intensity compared to morphine, but methadone was associated with a considerably prolonged or protracted withdrawal syndrome when compared to morphine. Morphine produced higher rates of self-administration and reinforcing behaviour in both human and animal subjects when compared to both methadone and pethidine. In comparison to equianalgesic doses of pethidine (Demerol), methadone was shown to produce less euphoria, but higher rates of constipation, and roughly equal levels of respiratory depression and sedation.

In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.

Isomethadone, noracymethadol, LAAM, and normethadone were first developed in Germany, the United Kingdom, Belgium, Austria, Canada, and the United States in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine. These synthetic opioids have increased length and depth of satiating any opiate cravings and generate very strong analgesic effects due to their long metabolic half-life and strong receptor affinity at the mu-opioid receptor sites. Therefore, they impart much of the satiating and anti-addictive effects of methadone by suppressing drug cravings.

It was only in 1947 that the drug was given the generic name "methadone" by the Council on Pharmacy and Chemistry of the American Medical Association. Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected, each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (MOLL 1990).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine. An urban myth later arose that Nazi leader Adolf Hitler ordered the manufacture of methadone or that the brand name 'Dolophine' was named after him, probably based on the similarity of "doloph" with "Adolph". (The pejorative term "adolphine" would appear in the early 1970s.) However, the name "Dolophine" was a contraction of "Dolo" from the Latin word dolor (pain), and finis, the Latin word for "end". Therefore, Dolophine literally means "pain end".

Methadone was studied as a treatment for opioid addiction at the Addiction Research Center of the Narcotics Farm in Lexington, Kentucky in the 1950s, and by Rockefeller University physicians Robert Dole and Marie Nyswander in the 1960s in New York City. By 1976, methadone clinics had opened in cities including Chicago, New York, and New Haven, with some 38,000 patients treated in New York City alone.