mitogen
Bluelighter
- Joined
- Nov 8, 2004
- Messages
- 127
Thought this might be interesting:
“Opium teaches only one thing, which is that aside from physical suffering, there is nothing real.” – André Malraux.
Pharmacology & Diversity of Opioids:
Opioid Diversity:
An important concept in opioid pharmacology is that different opioid drugs have different spectra of effects. Some opioids produce marked sedation, while others are not particularly sedating at all. Opioid drugs such as methadone and buprenorphine produced for maintenance purposes are not supposed to produce a ‘high’ in individuals who are addicted to more powerful (usually illicit) drugs [1, 2]. Conversely, some opioids such as hydromorphone (Dilaudid) are prized by addicts for the intense rush that injecting them gives the user. Other sources of variation are potency and efficacy: some drugs such as tramadol and buprenorphine are ‘partial agonists,’ while other opioids can be up to 10000x more potent than morphine, such as fentanyl [2]. These varying properties are usually a function of the physicochemical of each drug and how it interacts with receptors.
In this section, I will describe how opioid drugs have different affinities for each of the three major types of receptor, and may interact differently with these receptors.
In addition, I will discuss the contribution of some of the most recent advances in the field of opioid pharmacology, such as agonist directed trafficking and receptor complex and subtype diversity, and how these new concepts contribute to diversity of opioid drugs. It is worth noting that these concepts are quite general in pharmacology, and can easily be applied to other drugs of abuse; nicotine is a good example of a drug whose pharmacology in different regions of the brain is dependent on the receptor biology in that region.
Opioid Chemistry:
The first point of interest when attempting to decipher opioid diversity is to take a look at the chemistry of opioid drugs. To primary groups of opioid drugs exist [2]: the first includes morphine analogs, which are either directly derived from the opium poppy, such as codeine and morphine, or semi-synthetic derivatives of morphine like heroin and oxycodone. The second group comprises drugs which act at opioid receptors but whose structures are not related to morphine: phenylpiperidine drugs like fentanyl, methadone-like drugs such as methadone and dextropropoxyphene, benzomorphans such as pentazocine, and thebaine derivatives like etorphine and buprenorphine.
Fig1. A heroin molecule. [6] Note the acetyl groups – these are simply hydroxyl groups in morphine. It is proposed that these modifications increase the ability of the molecule to pass through the blood brain barrier, thereby increasing its CNS activity [2].
Literally thousands of synthetic opioid drugs have been created from the both framework of morphine and other structurally distinct opiates, and totally synthetic frameworks. The majority of these drugs would not be safe for human use, owing to either their high potency or other toxic effects. This myriad of man-made opioids would all have different effects, owing to their chemical structure.
Opioid Receptors:
Opioid receptors are the primary sites of action of opioid drugs. Some opioids are not entirely specific to opioid receptors, such as tramadol [2], which acts at 5HT and noradrenaline reuptake transporters in addition to being a partial Mu agonist; the majority of clinically used opioids are specific however. The main opioid receptor types have been found so far: the so-called ‘mu,’ ‘kappa’ and ‘delta’ receptors. Other putative opioid receptors exist, such as ‘sigma’ and ‘ORL-1’ (opioid receptor like receptor-1.) [2]
All of these receptors are part of the serpentine 7TMS GPCR (G-protein coupled receptor) family, and are coupled to Gi/o G-proteins [2]. Activation of Gi/o G-proteins inhibits production of cAMP by adenylate cyclase, causes opening of inwardly rectifying K+ channels and inhibits opening of Ca++ channels, resulting in cell hyperpolarisation and downstream signalling by cAMP, amongst other complex effects [2]. Variation in the relative affinity of opioid drugs for each of these receptor types is an important factor mediating diversity in opioid pharmacology.
The majority of clinically and illicitly used opioid drugs are relatively specific to mu receptors, with usually low but varying affinity for kappa and delta receptors [1,2].
Both the useful clinical effects (analgesia) and most of the unwanted (legal and toxic) effects, including those involved in abuse of opioid drugs, e.g. euphoria, sedation, dependence, respiratory depression, have been shown to be mediated primarily by mu receptors [1,2].
Kappa receptors contribute to analgesia at the level of the spinal cord, and also may produce some sedation and dysphoria, but dependence on drugs which act at kappa receptors is quite rare [2]. The majority of tests on kappa drugs have been done on animal models, so it may be difficult to assess their abuse potential in humans. The kappa receptor system is involved in tolerance to mu agonists, as will be discussed later in the section on tolerance to opioids [7]. Buprenorphine is both a partial agonist at mu receptors and an antagonist at kappa receptors. It is unknown exactly how much of a contribution to the effect of the drug that its kappa antagonist property has, but it is proposed to be important in helping the addict’s brain return to a pre-dependent state [16]. Additionally, some kappa specific analgesics have been developed [2].
Activation of delta receptors can produce some analgesia at the spinal level, and also may contribute to respiratory depression and reduced gut motility [2].
Agonist Directed Trafficking:
Agonist directed trafficking (ADT) is the concept that molecules with different physicochemical properties induce different conformations (a particular structural arrangement,) in the receptors to which they bind [4]. Classic GPCR theory dictates that there are only two receptor conformation states: active and inactive. ADT adds to complexity in opioid diversity by showing that the conformation induced in a receptor by a drug is plastic and depends on the drug. The conformation of the receptor is essential in dictating which to proteins in the post synaptic density, in what manner, and with what kinetics the receptor will bind [4]. Mu receptors, for example, are coupled to Gi/o G-proteins; there are many different types of Gi and Go proteins, and different receptor conformations will bind different combinations of these [4]. The end effect is that the downstream signalling pathways induced by the drug’s action on the receptor can differ from drug to drug. This could produce a difference in the subjective effects of opioids and different profiles of opioid drugs with respect to phenomena such as tolerance. Morphine, for example, does not induce the receptor downregulation that other opioids (such as some endogenous agonists) do [3].
Receptor Complexes:
Recently, GPCR’s (including opioid receptors) have been shown to form hetero- and homo- dimers and oligomers. Many studies have shown synergy and unexplained interactions between the pharmacology of different opioid receptor types. Investigation of dimerization and oligomerization phenomena may be able to explain some anomalous results by exploring the pharmacology of these complexes. Receptor oligomers may have completely different agonist specificity to their individual components, or may induce different downstream signalling pathways. [8]
Mu Receptor Subtypes:
The fact that some Mu specific agonist drugs exhibit incomplete cross-tolerance may be a clue that these drugs may not be actually acting at the same receptors. In one study, mice tolerant to morphine exhibted normal responses to morphine-6-glucuronide, fentanyl and heroin. Early binding studies actually identified two distinct binding components of both mu antagonist and agonist binding that differed in their affinities as well as selectivities for these drugs. Only one of these two sites were shown to be sensitive to the antagonist naloxonazine. Another antagonist beta-FNA antagonised all the effects of morphine, whilst naloxonazine had no effect on morphine respiratory depression or inhibition of GI tract motility. [5]
Opioid Pathways in the Brain:
Equally relevant to the pharmacology of opioid drugs is the location of receptors and pathways in the brain. Some attempt can be made to correlate the presence of receptors in specific parts of the brain with the function of the particular brain region to give some idea of how opioids may produce certain behaviours. This is in some respects overly ambitious; care must be taken, as non-holistic views of neuroscience can produce so many artefacts as to render these kinds of deductions false or irrelevant.
The brain has extensive networks of neurons which use a wide variety of endogenous opioid peptides as their transmitters. These peptides tend to be selective to a particular receptor type. Again, in this analysis I will concentrate on mu receptors.
Mu receptors are widely distributed throughout the brain and spinal cord, and also in the peripheral nervous system [7].
Fig2. is a schematic of the rat brain showing the location of opioidergic pathways. Also of note are the primary dopamine (DA) pathways in the brain, with which opioidergic neurons have extensive interaction, and the sites of nicotinic receptors, which fulfil an important neuromodulatory function on DA and opioidergic neurons.
Fig2. Opioidergic and dopaminergic pathways in the rat brain [7].
The periaqueductal gray (PAG) is important in pain sensation and neurons in this region heavily express opioid receptors [2]. The PAG is therefore obviously a primary site of opioid induced supraspinal analgesia. There is a long-standing debate concerning whether opioid analgesics actually relieve pain, that is, prevent nociceptive (painful) stimuli from becoming conscious, or whether their action is more in the manner of relieving suffering, which is the affective (mood-related) response to pain. A combination of the two actions seems the most likely explanation for opioid analgesia. Some pain patients given moderate doses of morphine are still able to describe the locus and intensity of pain, but report that they are no longer troubled by it; while others report that the pain is entirely gone [17]. The ventral tegmental area (VTA) and nucleus accumbens (NAc) are components of the mesolimbic ‘reward pathway’ and are involved in development of drug dependence and drug seeking behaviour [1,2,7]. The hippocampus and amygdala are components of the limbic system which plays a role in emotion and motivational drive [1,2].
The lateral hypothalamus and locus coeruleus are also important in mediating the effects of opioids. It is possible that the sedative effects of opioids may be mediated by their effect on the locus coeruleus, which is a part of the reticular activating system, a brain region crucial to wakefulness and attention [1].
Positive Aspects & Benefits of Opioid Use:
Morphine was one of the first drugs in the western pharmacoepia that was actually active. Since then it has been prescribed for a myriad of reasons.
The most obvious medical indication for opioids is pain. Opium was also extremely useful for treating dysentery. Apart from medically sanctioned use, users of illicit or black market prescription opioid drugs may use them because they feel that they confer benefits. The use of opioids in treating depressive and psychotic disorders has been quite well documented [9], but ethical considerations dictate that doctors do not prescribe opioid drugs for these disorders. Some people are genetically and/or environmentally predisposed to opioid dependence. It is possible that for these people, opioids may help, or even be the only treatment option that actually works. This website: http://www.geocities.com/HotSpring//9740/mystory.html is an amateur personal website detailing an account of a woman’s experiences with opiate addiction and manic depression, and describes how heroin was the only drug that had any significant effect on her condition. She subsequently transferred to methadone, and, apart from the demoralising nature of methadone clinics and the way she was treated by physicians, she found that methadone was a panacea to her depression. This kind of story is not uncommon, however a lot of research into opioids as antidepressants has been stifled.
Harms & Complications of Illicit Opioid Use:
In this section I will discuss some of the harms and risks associated with use of illicit opioids. The next section will move talk about how the objectives of opioid substitution treatment can help reduce these harms.
While self-medication with opioids is common, the harmful aspects of using illicit opioids will more often than not reduce the ability of a user to function and be happy. Many of these harms are associated with intravenous opioid use, and can include risk of contracting infectious diseases, damage to veins at injection sites, clogging of blood vessels by adulterants, and overdose. I will concentrate on the harmful effects of intoxication, tolerance, withdrawal and dependence.
Intoxication:
An individual who is severely intoxicated with an opioid drug will appear unconscious and will likely be quite unresponsive to stimuli. Obviously, this individual will be completely unable to drive a car or operate heavy machinery. Physiologically, intoxication with opioid drugs is not particularly harmful when compared with, for example, damage to the liver by ethanol, methamphetamine induced neurotoxicity or cocaine induced cardiotoxicity [11].
Constipation can be a problem and may exacerbate conditions such as haemarroids.
The possibility of overdose is the most important harmful effect of opioid intoxication.
Tolerance:
Tolerance to opioids escalates hugely over time. The primary problem associated with tolerance is that it can be variable. This variability can be dependent on the physiological or mental health state of the user, and other factors such as whether the user is in their ‘comfort zone’ – the place where they usually dose, or whether they are dosing in a completely unfamiliar environment. When the dose is taken in a familiar environment, the body and brain will often ‘get ready’ for the dose. Sometimes addicts take their normal morning dose and, due to a sudden unexpected drop in tolerance, they overdose [6, heroin experience reports].
Another problem with tolerance is the effect that requirement of massive doses has on the individual’s lifestyle. Old, tolerant junkies are usually penniless because they have to spend all their money on opiates.
Fig3. shows how dynorphin / kappa receptor mediated feedback in the mesolimbic dopamine pathway is dependent on upregulation of cAMP production that occurs in NAc projection neurons of opioid users.
Fig3. Regulation of CREB by drugs of abuse. Involvement of the dynorphin / kappa opioid system in development of tolerance to mu agonists.
Overdose:
The constant risk of overdose is such a significant part of the life of an opioid user that it warrants its own section. Overdose usually happens for one of three reasons: a.) suicide, b.) misjudgement of tolerance, c.) a stronger form of the drug than the addict is used to. Anecdotal evidence describes an increase in incidence of overdose when a particularly strong (pure) batch of heroin comes into an area.
Withdrawal:
Withdrawal from opioids can be exceptionally unpleasant. There are no direct harms associated with withdrawal – it is only rarely fatal, usually if the person is old and weak or sick from AIDS or hepatitis. The main problem with the withdrawal syndrome produced by opioids is that it provides negative reinforcement to keep taking the drug. Relapse to drug use after a period of withdrawal can reduce tolerance significantly, and may result in an overdose. Symptoms of withdrawal include: “watering eyes, runny nose, yawning, sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhoea, increased blood pressure and heart rate, chills, cramps and muscle aches, which can last 7–10 days” [1].
Withdrawal from methadone takes longer than heroin or morphine to develop and longer to diminish due to its longer half-life [2].
Dependence:
Substance dependence is defined by the DSM-IV index. Some opioid users become so dependent that may never successfully quit using, and require either illicit opioid or medical maintenance for the rest of their lives. Many of the health risks associated with chronic dependence on illicit opioids are a result of the fact that the drugs are illegal. Massive amounts of morphine are produced every year for both legal and illegal use. The street price of illegal opioids is extremely high compared to the market price of medical morphine. The majority of crime associated with opioid dependence could be eliminated if illicit forms of these substances were not so expensive. Street drugs are often ‘cut’ with dangerous adulterants.
The health risks caused by extreme poverty among street addicts who are hopelessly dependent, could also be ameliorated by providing these users with known doses of a cheap, pure pharmaceutical substitute. In addition, addicts have to associate with the often violent criminal underworld to obtain drugs.
In New Zealand, the most commonly abused form of opiate is pharmaceutical morphine ‘doubled’ or ‘turned’ with acetic anhydride to make a mix of diacetylmorphine (heroin) and dimeric monoacetylmorphine. The price is approximately $100/mg, and the classic MST or MScontin pills are filled with binders which make them hazardous to inject. Recognition of this situation has lead to development of pills which are not so hazardous to inject.
Pharmacology of Drugs Used in Treatment of Opioid Related Conditions:
Buprenorphine:
Buprenorphine (Bp) is a partial agonist at the mu opioid receptor. The receptor-drug complex is stable and dissociates slowly. Bp is more potent (~30x) than morphine and at equianalgesic doses, the duration of action of Bp is four times longer than morphine. Bp has a low dependence liability: “In chronically-treated primates neither abrupt withdrawal nor administration of narcotic antagonists could precipitate abstinence.” Bp may induce withdrawal symptoms in opioid addicts due to its partial agonistic effects.
Methadone:
Methadone has a longer half life (1-1.5 days) than most commonly abused opioids. This makes it useful in stabilising addicts as dosing is required only once a day.
For oral doses of 10-60 mg, the bioavailability of methadone is around 70-80% within a range of 36-100%. In New Zealand, larger doses are usually used, however the data for bioavailability should be consistent at higher doses. Methadone can reduce the effects of opiates of abuse by competitive antagonsim at the mu receptor. Tapered doses of methadone can be used to wean dependent individuals off opioids, but it is most often used over long periods for opioid maintenance therapy.
Naloxone:
Naloxone is a competitive antagonist (i.e. competes for the same binding site) at the mu opioid receptor. The primary indication for Naloxone administration is opioid overdose. Naloxone can reverse opioid induced respiratory depression and has been used since the 70’s to save the lives of opioid users. Additionally, Naloxone is sometimes prescribed post-detox, so that if the patient lapses and tries to take an opioid, the effects will be blocked.
Clonidine:
Clonidine is an alpha 2 adrenoreceptor agonist, and is used to reduce the noradrenergic symptoms of acute opioid withdrawal. Clonidine can aid insomnia, withdrawal induced hypertension and the unpleasant effects of noradrenaline mediated autonomic symptoms, such as sweating and lacrimation. Unfortunately, Clonidine has potentially dangerous side effects, such as dose dependent hypotension.
Opioid References:
1.) World Health Organisation Report: Neuroscience of Psychoactive Substance Use and Dependence 2004
2.) Rang HP, Dale MM, Ritter JM, Moore PK “Pharmacology” 5th edition, Churchill Livingstone, Elsevier Science 2003
3.) Opioid agonists differentially regulate mu-opioid receptors and trafficking proteins in vivo.
4.) Brink, Harvey, Bodenstein, Venter, Oliver “Recent advances in drug action and therapeutics: Relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology” British Journal of Pharmacology, 2004 57:4 373-387
5.) Pasternak G, “Insights into mu opioid pharmacology. The role of mu opioid receptor subtypes.” Life Sciences 68 (2001) 2213-2219
6.) www.erowid.org
7.) Nestler E. “Molecular basis of long term plasticity underlying addiction.” Nature Reviews Neuroscience Volume 2 Feb 2001
8.) George S, Fan T, Xie Z, Tse R, Tam V, Varghese G, O’Dowd B “Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties.” Journal of Biological Chemistry Aug 25;275(34) 26128-25
9.) Gold M, Pottash A, Sweeney D, martin D, Extein I. “Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence.” Ann N Y Acad Sci. 1982;398:140-50.
10.) Von Zastrow M. “A cell biologist’s perspective on physiological adaptation to opiate drugs” Neuropharmacology 47 (2004) 286-292
11.) Ball J, Urbaitis J. “Absence of major medical complications among chronic opiate addicts.” Br J Addict Alcohol Other Drugs 1970 Aug;65(2):109-12
12.) NZ medsafe data sheets, Buprenorphine, http://www.medsafe.govt.nz/profs/Datasheet/t/Temgesicinj.htm
13.) Hong Kong Govt. Website on AIDS Harm Reduction http://www.info.gov.hk/aids/harmreduction/workshop2003/pdf/5a-s3-1.pdf
14.) NZ Medsafe Data Sheet, Naloxone, http://www.medsafe.govt.nz/profs/Datasheet/n/Naloxonehydrochlorideinj.htm
15.) Micromedex database DRUG CONSULTS: DRUG THERAPY OF OPIOID WITHDRAWAL
16.) Riley AL, Pournaghash S. “The effects of chronic morphine on the generalization of buprenorphine stimulus control: an assessment of kappa antagonist activity.” Pharmacol Biochem Behav. 1995 Dec;52(4):779-87.
17.) Eaton T. Fores Research Center “The story of the poppy and all that followed from it.”
“Opium teaches only one thing, which is that aside from physical suffering, there is nothing real.” – André Malraux.
Pharmacology & Diversity of Opioids:
Opioid Diversity:
An important concept in opioid pharmacology is that different opioid drugs have different spectra of effects. Some opioids produce marked sedation, while others are not particularly sedating at all. Opioid drugs such as methadone and buprenorphine produced for maintenance purposes are not supposed to produce a ‘high’ in individuals who are addicted to more powerful (usually illicit) drugs [1, 2]. Conversely, some opioids such as hydromorphone (Dilaudid) are prized by addicts for the intense rush that injecting them gives the user. Other sources of variation are potency and efficacy: some drugs such as tramadol and buprenorphine are ‘partial agonists,’ while other opioids can be up to 10000x more potent than morphine, such as fentanyl [2]. These varying properties are usually a function of the physicochemical of each drug and how it interacts with receptors.
In this section, I will describe how opioid drugs have different affinities for each of the three major types of receptor, and may interact differently with these receptors.
In addition, I will discuss the contribution of some of the most recent advances in the field of opioid pharmacology, such as agonist directed trafficking and receptor complex and subtype diversity, and how these new concepts contribute to diversity of opioid drugs. It is worth noting that these concepts are quite general in pharmacology, and can easily be applied to other drugs of abuse; nicotine is a good example of a drug whose pharmacology in different regions of the brain is dependent on the receptor biology in that region.
Opioid Chemistry:
The first point of interest when attempting to decipher opioid diversity is to take a look at the chemistry of opioid drugs. To primary groups of opioid drugs exist [2]: the first includes morphine analogs, which are either directly derived from the opium poppy, such as codeine and morphine, or semi-synthetic derivatives of morphine like heroin and oxycodone. The second group comprises drugs which act at opioid receptors but whose structures are not related to morphine: phenylpiperidine drugs like fentanyl, methadone-like drugs such as methadone and dextropropoxyphene, benzomorphans such as pentazocine, and thebaine derivatives like etorphine and buprenorphine.
Fig1. A heroin molecule. [6] Note the acetyl groups – these are simply hydroxyl groups in morphine. It is proposed that these modifications increase the ability of the molecule to pass through the blood brain barrier, thereby increasing its CNS activity [2].
Literally thousands of synthetic opioid drugs have been created from the both framework of morphine and other structurally distinct opiates, and totally synthetic frameworks. The majority of these drugs would not be safe for human use, owing to either their high potency or other toxic effects. This myriad of man-made opioids would all have different effects, owing to their chemical structure.
Opioid Receptors:
Opioid receptors are the primary sites of action of opioid drugs. Some opioids are not entirely specific to opioid receptors, such as tramadol [2], which acts at 5HT and noradrenaline reuptake transporters in addition to being a partial Mu agonist; the majority of clinically used opioids are specific however. The main opioid receptor types have been found so far: the so-called ‘mu,’ ‘kappa’ and ‘delta’ receptors. Other putative opioid receptors exist, such as ‘sigma’ and ‘ORL-1’ (opioid receptor like receptor-1.) [2]
All of these receptors are part of the serpentine 7TMS GPCR (G-protein coupled receptor) family, and are coupled to Gi/o G-proteins [2]. Activation of Gi/o G-proteins inhibits production of cAMP by adenylate cyclase, causes opening of inwardly rectifying K+ channels and inhibits opening of Ca++ channels, resulting in cell hyperpolarisation and downstream signalling by cAMP, amongst other complex effects [2]. Variation in the relative affinity of opioid drugs for each of these receptor types is an important factor mediating diversity in opioid pharmacology.
The majority of clinically and illicitly used opioid drugs are relatively specific to mu receptors, with usually low but varying affinity for kappa and delta receptors [1,2].
Both the useful clinical effects (analgesia) and most of the unwanted (legal and toxic) effects, including those involved in abuse of opioid drugs, e.g. euphoria, sedation, dependence, respiratory depression, have been shown to be mediated primarily by mu receptors [1,2].
Kappa receptors contribute to analgesia at the level of the spinal cord, and also may produce some sedation and dysphoria, but dependence on drugs which act at kappa receptors is quite rare [2]. The majority of tests on kappa drugs have been done on animal models, so it may be difficult to assess their abuse potential in humans. The kappa receptor system is involved in tolerance to mu agonists, as will be discussed later in the section on tolerance to opioids [7]. Buprenorphine is both a partial agonist at mu receptors and an antagonist at kappa receptors. It is unknown exactly how much of a contribution to the effect of the drug that its kappa antagonist property has, but it is proposed to be important in helping the addict’s brain return to a pre-dependent state [16]. Additionally, some kappa specific analgesics have been developed [2].
Activation of delta receptors can produce some analgesia at the spinal level, and also may contribute to respiratory depression and reduced gut motility [2].
Agonist Directed Trafficking:
Agonist directed trafficking (ADT) is the concept that molecules with different physicochemical properties induce different conformations (a particular structural arrangement,) in the receptors to which they bind [4]. Classic GPCR theory dictates that there are only two receptor conformation states: active and inactive. ADT adds to complexity in opioid diversity by showing that the conformation induced in a receptor by a drug is plastic and depends on the drug. The conformation of the receptor is essential in dictating which to proteins in the post synaptic density, in what manner, and with what kinetics the receptor will bind [4]. Mu receptors, for example, are coupled to Gi/o G-proteins; there are many different types of Gi and Go proteins, and different receptor conformations will bind different combinations of these [4]. The end effect is that the downstream signalling pathways induced by the drug’s action on the receptor can differ from drug to drug. This could produce a difference in the subjective effects of opioids and different profiles of opioid drugs with respect to phenomena such as tolerance. Morphine, for example, does not induce the receptor downregulation that other opioids (such as some endogenous agonists) do [3].
Receptor Complexes:
Recently, GPCR’s (including opioid receptors) have been shown to form hetero- and homo- dimers and oligomers. Many studies have shown synergy and unexplained interactions between the pharmacology of different opioid receptor types. Investigation of dimerization and oligomerization phenomena may be able to explain some anomalous results by exploring the pharmacology of these complexes. Receptor oligomers may have completely different agonist specificity to their individual components, or may induce different downstream signalling pathways. [8]
Mu Receptor Subtypes:
The fact that some Mu specific agonist drugs exhibit incomplete cross-tolerance may be a clue that these drugs may not be actually acting at the same receptors. In one study, mice tolerant to morphine exhibted normal responses to morphine-6-glucuronide, fentanyl and heroin. Early binding studies actually identified two distinct binding components of both mu antagonist and agonist binding that differed in their affinities as well as selectivities for these drugs. Only one of these two sites were shown to be sensitive to the antagonist naloxonazine. Another antagonist beta-FNA antagonised all the effects of morphine, whilst naloxonazine had no effect on morphine respiratory depression or inhibition of GI tract motility. [5]
Opioid Pathways in the Brain:
Equally relevant to the pharmacology of opioid drugs is the location of receptors and pathways in the brain. Some attempt can be made to correlate the presence of receptors in specific parts of the brain with the function of the particular brain region to give some idea of how opioids may produce certain behaviours. This is in some respects overly ambitious; care must be taken, as non-holistic views of neuroscience can produce so many artefacts as to render these kinds of deductions false or irrelevant.
The brain has extensive networks of neurons which use a wide variety of endogenous opioid peptides as their transmitters. These peptides tend to be selective to a particular receptor type. Again, in this analysis I will concentrate on mu receptors.
Mu receptors are widely distributed throughout the brain and spinal cord, and also in the peripheral nervous system [7].
Fig2. is a schematic of the rat brain showing the location of opioidergic pathways. Also of note are the primary dopamine (DA) pathways in the brain, with which opioidergic neurons have extensive interaction, and the sites of nicotinic receptors, which fulfil an important neuromodulatory function on DA and opioidergic neurons.
Fig2. Opioidergic and dopaminergic pathways in the rat brain [7].
The periaqueductal gray (PAG) is important in pain sensation and neurons in this region heavily express opioid receptors [2]. The PAG is therefore obviously a primary site of opioid induced supraspinal analgesia. There is a long-standing debate concerning whether opioid analgesics actually relieve pain, that is, prevent nociceptive (painful) stimuli from becoming conscious, or whether their action is more in the manner of relieving suffering, which is the affective (mood-related) response to pain. A combination of the two actions seems the most likely explanation for opioid analgesia. Some pain patients given moderate doses of morphine are still able to describe the locus and intensity of pain, but report that they are no longer troubled by it; while others report that the pain is entirely gone [17]. The ventral tegmental area (VTA) and nucleus accumbens (NAc) are components of the mesolimbic ‘reward pathway’ and are involved in development of drug dependence and drug seeking behaviour [1,2,7]. The hippocampus and amygdala are components of the limbic system which plays a role in emotion and motivational drive [1,2].
The lateral hypothalamus and locus coeruleus are also important in mediating the effects of opioids. It is possible that the sedative effects of opioids may be mediated by their effect on the locus coeruleus, which is a part of the reticular activating system, a brain region crucial to wakefulness and attention [1].
Positive Aspects & Benefits of Opioid Use:
Morphine was one of the first drugs in the western pharmacoepia that was actually active. Since then it has been prescribed for a myriad of reasons.
The most obvious medical indication for opioids is pain. Opium was also extremely useful for treating dysentery. Apart from medically sanctioned use, users of illicit or black market prescription opioid drugs may use them because they feel that they confer benefits. The use of opioids in treating depressive and psychotic disorders has been quite well documented [9], but ethical considerations dictate that doctors do not prescribe opioid drugs for these disorders. Some people are genetically and/or environmentally predisposed to opioid dependence. It is possible that for these people, opioids may help, or even be the only treatment option that actually works. This website: http://www.geocities.com/HotSpring//9740/mystory.html is an amateur personal website detailing an account of a woman’s experiences with opiate addiction and manic depression, and describes how heroin was the only drug that had any significant effect on her condition. She subsequently transferred to methadone, and, apart from the demoralising nature of methadone clinics and the way she was treated by physicians, she found that methadone was a panacea to her depression. This kind of story is not uncommon, however a lot of research into opioids as antidepressants has been stifled.
Harms & Complications of Illicit Opioid Use:
In this section I will discuss some of the harms and risks associated with use of illicit opioids. The next section will move talk about how the objectives of opioid substitution treatment can help reduce these harms.
While self-medication with opioids is common, the harmful aspects of using illicit opioids will more often than not reduce the ability of a user to function and be happy. Many of these harms are associated with intravenous opioid use, and can include risk of contracting infectious diseases, damage to veins at injection sites, clogging of blood vessels by adulterants, and overdose. I will concentrate on the harmful effects of intoxication, tolerance, withdrawal and dependence.
Intoxication:
An individual who is severely intoxicated with an opioid drug will appear unconscious and will likely be quite unresponsive to stimuli. Obviously, this individual will be completely unable to drive a car or operate heavy machinery. Physiologically, intoxication with opioid drugs is not particularly harmful when compared with, for example, damage to the liver by ethanol, methamphetamine induced neurotoxicity or cocaine induced cardiotoxicity [11].
Constipation can be a problem and may exacerbate conditions such as haemarroids.
The possibility of overdose is the most important harmful effect of opioid intoxication.
Tolerance:
Tolerance to opioids escalates hugely over time. The primary problem associated with tolerance is that it can be variable. This variability can be dependent on the physiological or mental health state of the user, and other factors such as whether the user is in their ‘comfort zone’ – the place where they usually dose, or whether they are dosing in a completely unfamiliar environment. When the dose is taken in a familiar environment, the body and brain will often ‘get ready’ for the dose. Sometimes addicts take their normal morning dose and, due to a sudden unexpected drop in tolerance, they overdose [6, heroin experience reports].
Another problem with tolerance is the effect that requirement of massive doses has on the individual’s lifestyle. Old, tolerant junkies are usually penniless because they have to spend all their money on opiates.
Fig3. shows how dynorphin / kappa receptor mediated feedback in the mesolimbic dopamine pathway is dependent on upregulation of cAMP production that occurs in NAc projection neurons of opioid users.
Fig3. Regulation of CREB by drugs of abuse. Involvement of the dynorphin / kappa opioid system in development of tolerance to mu agonists.
Overdose:
The constant risk of overdose is such a significant part of the life of an opioid user that it warrants its own section. Overdose usually happens for one of three reasons: a.) suicide, b.) misjudgement of tolerance, c.) a stronger form of the drug than the addict is used to. Anecdotal evidence describes an increase in incidence of overdose when a particularly strong (pure) batch of heroin comes into an area.
Withdrawal:
Withdrawal from opioids can be exceptionally unpleasant. There are no direct harms associated with withdrawal – it is only rarely fatal, usually if the person is old and weak or sick from AIDS or hepatitis. The main problem with the withdrawal syndrome produced by opioids is that it provides negative reinforcement to keep taking the drug. Relapse to drug use after a period of withdrawal can reduce tolerance significantly, and may result in an overdose. Symptoms of withdrawal include: “watering eyes, runny nose, yawning, sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhoea, increased blood pressure and heart rate, chills, cramps and muscle aches, which can last 7–10 days” [1].
Withdrawal from methadone takes longer than heroin or morphine to develop and longer to diminish due to its longer half-life [2].
Dependence:
Substance dependence is defined by the DSM-IV index. Some opioid users become so dependent that may never successfully quit using, and require either illicit opioid or medical maintenance for the rest of their lives. Many of the health risks associated with chronic dependence on illicit opioids are a result of the fact that the drugs are illegal. Massive amounts of morphine are produced every year for both legal and illegal use. The street price of illegal opioids is extremely high compared to the market price of medical morphine. The majority of crime associated with opioid dependence could be eliminated if illicit forms of these substances were not so expensive. Street drugs are often ‘cut’ with dangerous adulterants.
The health risks caused by extreme poverty among street addicts who are hopelessly dependent, could also be ameliorated by providing these users with known doses of a cheap, pure pharmaceutical substitute. In addition, addicts have to associate with the often violent criminal underworld to obtain drugs.
In New Zealand, the most commonly abused form of opiate is pharmaceutical morphine ‘doubled’ or ‘turned’ with acetic anhydride to make a mix of diacetylmorphine (heroin) and dimeric monoacetylmorphine. The price is approximately $100/mg, and the classic MST or MScontin pills are filled with binders which make them hazardous to inject. Recognition of this situation has lead to development of pills which are not so hazardous to inject.
Pharmacology of Drugs Used in Treatment of Opioid Related Conditions:
Buprenorphine:
Buprenorphine (Bp) is a partial agonist at the mu opioid receptor. The receptor-drug complex is stable and dissociates slowly. Bp is more potent (~30x) than morphine and at equianalgesic doses, the duration of action of Bp is four times longer than morphine. Bp has a low dependence liability: “In chronically-treated primates neither abrupt withdrawal nor administration of narcotic antagonists could precipitate abstinence.” Bp may induce withdrawal symptoms in opioid addicts due to its partial agonistic effects.
Methadone:
Methadone has a longer half life (1-1.5 days) than most commonly abused opioids. This makes it useful in stabilising addicts as dosing is required only once a day.
For oral doses of 10-60 mg, the bioavailability of methadone is around 70-80% within a range of 36-100%. In New Zealand, larger doses are usually used, however the data for bioavailability should be consistent at higher doses. Methadone can reduce the effects of opiates of abuse by competitive antagonsim at the mu receptor. Tapered doses of methadone can be used to wean dependent individuals off opioids, but it is most often used over long periods for opioid maintenance therapy.
Naloxone:
Naloxone is a competitive antagonist (i.e. competes for the same binding site) at the mu opioid receptor. The primary indication for Naloxone administration is opioid overdose. Naloxone can reverse opioid induced respiratory depression and has been used since the 70’s to save the lives of opioid users. Additionally, Naloxone is sometimes prescribed post-detox, so that if the patient lapses and tries to take an opioid, the effects will be blocked.
Clonidine:
Clonidine is an alpha 2 adrenoreceptor agonist, and is used to reduce the noradrenergic symptoms of acute opioid withdrawal. Clonidine can aid insomnia, withdrawal induced hypertension and the unpleasant effects of noradrenaline mediated autonomic symptoms, such as sweating and lacrimation. Unfortunately, Clonidine has potentially dangerous side effects, such as dose dependent hypotension.
Opioid References:
1.) World Health Organisation Report: Neuroscience of Psychoactive Substance Use and Dependence 2004
2.) Rang HP, Dale MM, Ritter JM, Moore PK “Pharmacology” 5th edition, Churchill Livingstone, Elsevier Science 2003
3.) Opioid agonists differentially regulate mu-opioid receptors and trafficking proteins in vivo.
4.) Brink, Harvey, Bodenstein, Venter, Oliver “Recent advances in drug action and therapeutics: Relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology” British Journal of Pharmacology, 2004 57:4 373-387
5.) Pasternak G, “Insights into mu opioid pharmacology. The role of mu opioid receptor subtypes.” Life Sciences 68 (2001) 2213-2219
6.) www.erowid.org
7.) Nestler E. “Molecular basis of long term plasticity underlying addiction.” Nature Reviews Neuroscience Volume 2 Feb 2001
8.) George S, Fan T, Xie Z, Tse R, Tam V, Varghese G, O’Dowd B “Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties.” Journal of Biological Chemistry Aug 25;275(34) 26128-25
9.) Gold M, Pottash A, Sweeney D, martin D, Extein I. “Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence.” Ann N Y Acad Sci. 1982;398:140-50.
10.) Von Zastrow M. “A cell biologist’s perspective on physiological adaptation to opiate drugs” Neuropharmacology 47 (2004) 286-292
11.) Ball J, Urbaitis J. “Absence of major medical complications among chronic opiate addicts.” Br J Addict Alcohol Other Drugs 1970 Aug;65(2):109-12
12.) NZ medsafe data sheets, Buprenorphine, http://www.medsafe.govt.nz/profs/Datasheet/t/Temgesicinj.htm
13.) Hong Kong Govt. Website on AIDS Harm Reduction http://www.info.gov.hk/aids/harmreduction/workshop2003/pdf/5a-s3-1.pdf
14.) NZ Medsafe Data Sheet, Naloxone, http://www.medsafe.govt.nz/profs/Datasheet/n/Naloxonehydrochlorideinj.htm
15.) Micromedex database DRUG CONSULTS: DRUG THERAPY OF OPIOID WITHDRAWAL
16.) Riley AL, Pournaghash S. “The effects of chronic morphine on the generalization of buprenorphine stimulus control: an assessment of kappa antagonist activity.” Pharmacol Biochem Behav. 1995 Dec;52(4):779-87.
17.) Eaton T. Fores Research Center “The story of the poppy and all that followed from it.”
![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
