Addiction Treatment Blog

If opium-eating be a sensual pleasure, and if I am bound to confess that I have indulged in it to an excess not yet recorded of any other man, it is in no less true that I have struggled against this fascination with a fervent zeal, and have at length accomplished what I never yet heard attributed to any other man, have untwisted, almost to its final links, the chain which fettered me.

Thomas de Quincy, ‘Confessions of an English Opium Eater’, 1821

History

Opiates were originally available from the opium poppy (Papaver somniferum), native to Asia Minor. The active constituents can be found in the latex which exudes from incisions in the unripe capsule of the flowering head. The alkaloids which occur in the poppy include morphine, noscapine, codeine, papaverine and thebaine. Strictly speaking, alkaloids derived from the opium poppy which have morphine-like actions are termed opiates, whereas opioids are synthetic derivatives, e.g. methadone. However, in recent times the term opioid has been understood to encompass opiates.

Heads of opium poppies

Morphine is responsible for most of the psychotropic activity and comprises some 9 to 17 per cent if the weight of dried opium but is usually about 10 per cent. Opium itself has been used by man for thousands of years, both as medicine and as an intoxicant. It was cultivated in many places in Neolithic Europe, where it may have been burned to produce an intoxicating smoke. However, in most cultures, opium was usually taken orally. Smoking of opium using an individual pipe probably originated in China in the 17th century and a huge population of dependent individuals began to develop there. Opium was subsequently the cause of two wars between Britain and China in the 19th century when the British continued to sell opium to the Chinese people despite a decree from the Emperor outlawing the use of it.

In the USA, the widescale of opium as an analgesic during the Civil War created many thousands of addicts. In both the USA and Great Britain opium purchased for ‘medicinal purposes’ and sold overtly to produce intoxication caused serious social problems in the 19th century. Many medicines that were freely sold over the counter for coughs, gastrointestinal complaints, sleep disorders etc. contained appreciable quantities of opium. The extent of this problem was not recognised for many years; it abated to some extent following legislation. The problem of opioid abuse has remained ever since, in one form or another. Today, most abuse is centred around heroin (diamorphine).

Morphine was first isolated in 1806 by a pharmacist, Wilhelm Serturner, and named after the Greek god of dreams, Morpheus. Like many products since, diamorphine was initially marketed (in 1898) as a ‘less addictive‘ form of an existing drug and only later was its true dependence potential realised.

Effects Sought

When heroin is injected the user commonly experiences a rapid feeling of intense pleasure. This euphoria is replaced by a feeling of warmth (resulting from peripheral vasodilation), relaxation and happiness – although some experience stimulatory effects. Unlike a variety of other central nervous system (CNS) depressants, does sufficient to cause euphoria do not impair movement (ataxia) or intellectual ability. Large doses produce sedation or a pleasant light sleep. The individual is able to detach himself from the ongoing concerns and pressures of real life. With chronic administration, however, the addict becomes tolerant to the psychotropic effects which were the original purpose of abuse. The object of each ‘fix’ then effectively  becomes to avoid withdrawal symptoms (negative reinforcement).

Smoking, vaporising or ‘snorting‘ heroin producers a milder ‘rush’ than intravenous injection. The oral route does not produce a ‘rush’ and is therefore unpopular. Non-heroin opioids produce similar but usually less intense effects, because of reduced CNS penetration and potency. The fentanyl derivatives are a notable exception.

Administration

Probably all of the opioids available medicinally have been abused to some extent. The heroin abused on the street today is made illegally in small-scale laboratories in the UK and abroad, and very little is diverted from legitimate medical sources. However, supplies of most other opioids are largely obtained through abuse of pharmaceutical products, e.g. methadone, buprenorphine, Diconal and dextropropoxyphene.

Heroin is the most widely used opioid, probably because of its potency, solubility in water and high biological lipophilicity, which affords rapid brain access. It is known as ‘junk‘, ‘H‘, ‘smack‘, ‘skag‘ or ‘horse‘. It is usually supplied as a brown or off-white powder, depending on the purity and the manufacturing process. It is always adulterated with other substances when bought at street level. The drug is progressively diluted (or ‘cut‘) as it moves down the line from manufacturer through various dealers to the end user. Adulterants include almost any powder, e.g. sugars, talcum powder, chalk, flour, salt and other drugs.

Diconal has a certain appeal because it contains an opioid, dipipanone, as well as cyclizine. The abuse of the antihistamine will be discussed on a later article.

Buprenorphine, a partial opioid agonist, was initially claimed to have low dependency potential and to produce only mild symptoms upon withdrawal. However, perhaps predictably, buprenorphine abuse eventually became so widespread in the UK that it forced the reclassification of this drug from prescription-only to controlled drug.

Dextropropoxyphene, dihydrocodeine and codeine are less popular at street level because they are weak opioids and because many pharmaceutical sources containing a sufficient amount of opioid also contain paracetamol or aspirin. Consequently, it is difficult to take enough of the opioid for intoxication without risking potentially fatal paracetamol/aspirin overdose. An exception to this is codeine linctus but it has volume required for intoxication prevents injection. Dextropropoxyphene, dihydrocodeine and codeine are weak opioids and only likely to be taken when more potent alternatives are not available, so that illicit synthesis is unlikely to be profitable. Nonetheless, these opioids are still abused, particularly codeine linctus. The abuse of over-the-counter opioids will be discussed in more detail at a later stage.

The methadone encountered at street level has been diverted from treatment clinics where the drug is prescribed as a substitute for street opioids in dependent individuals (see below). In the USA, illicit derivatives of fentanyl, a very potent opioid, have gained in popularity but these are not widely used in the UK (see below).

Most of the opioids can be administered orally, but the CNS effects are slow to develop and are blunted. In addition, all opioids are subject to some presystemic metabolism – the average bioavailability of oral buprenorphine is only 16 per cent, for example, whereas for morphine it is 40 to 50 per cent. Many addicts prefer the intravenous route as this produces an intense ‘rush’ of euphoria which does not occur following oral ingestion. A variety of unsuitable preparations are injected (or ‘fixed’), including heroin powder bought on the street, crushed opioid-containing tablets and liquid preparations (e.g. methadone elixir). For the purpose of injecting, street heroin is sometimes mixed by the abuser with simple organic acids (e.g. ascorbic acid, citric acid) to facilitate extraction of heroin from the mixture of inactive adulterants; occasionally lemon juice or vinegar is used. Persistent injection of non-sterile solutions which are contaminated with particles eventually causes blood vessel damage, which, in turn, severely restricts venous access. If this occurs, addicts may sometimes resort to subcutaneous injection.

Powdered heroin can be inhaled nasally (’snorted’), smoked in cigarettes (’reefers’) or heated on foil and the vapour inhaled (’chasing the dragon’ or ’skagging’). Non-injection forms of administration are becoming more common, particularly in new and younger heroin users. This is probably related to the fact that heroin supplies have become more pure in intravenous injection. This reduces the risk of AIDS due to shared injection equipment. It remains to be seen whether these novices will in time move toward injecting.

Pharmacokinetics and Pharmacology

Opioid receptors in the central nervous system mediate the actions of endogenous peptides such as enkephalins and dynorphins, which probably initiate or control a range of behaviours and moods. There may be up to five types of receptor. μ (mu), Κ (kappa), σ (sigma), δ (delta) and ε (epsilon). The euphoria and physical dependence attributable to opioids are thought to be mediated through μ receptors. Receptors outside the CNS facilitate some of the peripheral side effects of opioids, e.g. constipation and effects on renal blood flow.

The opioids are all metabolised principally in the liver and the metabolites are then excreted renally. Diamorphine (heroin) is unusual in that the molecule itself has no intrinsic actions at opioid receptors, all of its actions are due to its two main metabolites: 6-monoacetylmorphine and morphine. Diamorphine (or diacetylmorphine) is rapidly deacetylated in the liver, kidney, blood, brain and other tissues to form these metabolites, such that diamorphine has an average half-life of only three minutes; 6-monoacetylmorphine has a similarly short half-life. Morphine is converted to a range of metabolites in the liver and has an average half-life of about three hours. The two most important metabolites are formed by conjugation: morphine-3-glucuronide and morphine-6-glucuronide. The latter only compromises about 5 per cent of metabolites, but is a much more potent opioid agonist than morphine. All the morphine metabolites are excreted renally.

Adverse Effects

The adverse effects associated with opioid abuse fall into four distinct categories: side effects of opioid drugs, effects of overdose, adverse consequences of the abuse process and withdrawal symptoms.

The side effects of opioids are well-known and are listed in the table below. Tolerance develops to all of these dose-related effects except constipation. Thrombocytopenia has been reported, but may be an immune-based reaction to adulterants. Chronic administration tends to depress sexual desire and performance, although these may be enhanced in the initial stages of abuse.

Intoxication with opioids may increase the chance of the individual causing if the individual causing or being exposed to accidents. Disinhibition and subjectively enhanced sexual performance (expecially in the early stages of heroin use) can result in increased sexual activity and therefore increased risk of AIDS, other sexually-transmitted diseases or unwanted pregnancies.

Adverse Effects of Opioids

Common

• Nausea, vomiting, constipation
• Drowsiness, mental confusion

Infrequent

• Sweating, facial flushing, pruritus
• Dry mouth
• Hallucinations, dysphoria
• Urinary retention
• Headache

Rare

• Thrombocytopenia
• Rashes, urticaria
• Vertigo
• Palpitations, postural hypotension

The effects of overdose are given in the table below. All of these except arrhythmia and pulmonary oedema, may be reversed with the opioid antagonist naloxone, but at risk of precipitating acute opioid withdrawal. The dose of naloxone needs to be repeated because it has a shorter half-life than most opioids. Some drugs, such as dextropropoxyphene, methadone and buprenorphine, have particularly long half-lives and prolonged naloxone administration may therefore be required after overdose with these substances (up to 72 hours with methadone). Opioid overdose may occur with the intention of committing suicide. But it may arise by accident as a result of the unexpected potency of a sample purchased at street level or after a period of abstinence during which tolerance has decreased. The incidence of overdose amongst heroin users has been estimated at about one-quarter of the affected population in a London study, but two-thirds of the population in Sydney, Australia. Consequently it has recently been proposed that the opioid antagonist naloxone be supplied to street users of opioids.

Adverse effects arising from the abuse process include the harmful consequences of injection, which are discussed on Adverse Consequences in Drug Injection. There are also a large number of adverse social effects which result from opioid dependence, including increased likelihood of criminal activity, general poor health and diet, antisocial behaviour and disrupted relationships.

Signs and Symptoms of Opioid Overdose

• Dysphoria, hallucinations, heavy sedation
• Miosis
• Hypothermia
• Respiratory depression, pulmonary oedema, coma
• Hypotension, bradycardia, arrhythmias secondary to hypoxia
• Convulsions (dextropropoxyphene and pethidine only)

Opioid Dependence

Opioid dependence is a well-established and clearly defined phenomenon. It is characterised by physical dependence which becomes more likely as the dose and duration of administration increase. There are two essential components to this: receptor tolerance and a withdrawal reaction upon discontinuation.

Opioid addicts become tolerant to the pleasurable psychotropic effects quite rapidly. The dose is increased in an attempt to regain the lost experience. This is effective for a time, but tolerance redevelops and the dose is then progressively increased to a maximum, often determined by drug availability. At this level there is permanent tolerance to most of the effects of opioids, including euphoria, although complete tolerance to constipation and misois does not seem to occur. The drive to continue drug administration becomes the desire to avoid a withdrawal reaction (negative reinforcement) rather than the pleasure of the experience (positive reinforcement). Cross-tolerance exists between all the opioid drugs and so addicts may seek cheaper alternatives to street opioids in an attempt to stave off withdrawal when these are not available. Codeine linctus in particular is used for this purpose.

The opioid withdrawal syndrome is charactarised by a range of symptoms (see the table below). When an addict attempts to cease opioid administration abruptly, without medical support, he or she is said to be doing ‘cold turkey’. This is believed to originate from the gooseflesh appearance of the skin that is commonly seen in this situation. The symptoms of withdrawal manifest as the reverse of normal opioid action on the body, i.e. they are suggestive of CNS hyperactivity rather than depression. Although subjectively very unpleasant, these effects are not life-threatening, and the subject remains relatively lucid throughout.

Signs of heroin withdrawal may commence within six hours of abstinence, but the peak effects are seen after 36 to 72 hours, followed by gradual abatement over the subsequent 5 to 10 days. If opioid addicts are given naloxone, withdrawal may develop almost instantly.

This acute phase of withdrawal is followed by a period of relatively chronic symptoms usually characterised by a craving for opioids and accompanied by anxiety, emotional lability, depression, fatigue insomnia. These persistent effects can take months to abate, are very hard to ignore and may encourage a return to opioid abuse.

Recent work in animals has helped to elucidate the mechanisms of opioid withdrawal. The locus coerules in the brain seems to play particularly important part in mediating the physical signs of opioid withdrawal. Furthermore, the existence of anti-opioid peptides has been postulated. These peptides may be released in the CNS as a response to chronic exogenous opioid administration and therefore help to mediate tolerance. The excess anti-opioid peptides that remain following opioid discontinuation may at least be partly responsible for causing the symptoms of withdrawal.

Symptoms of Acute Opioid Withdrawal

Initial Symptoms

• Anxiety, restlessness, insomnia
• Mild tachypnoea, yawning, coughing, sneezing
• Craving for drug
• Lacrimation, perspiration, rhinorrhoea

Later Symptoms

• Tremors, myalgia, arthralgia, muscle twitching
• Chills, piloerection (gooseflesh), hot flushes
• Anorexia, abdominal pains
• Mydriasis
• Insomnia, headache

Severe Cases

• Tachycardia, hypertension or hypotension
• Nausea, vomiting, diarrhoea
• Fever, dehydration
• Severe or persistent tachypnoea
• Agitation

Treatment of Dependence and Withdrawal

Opioid dependence should not be seen as a hopeless cause. A 22-year follow-up of 128 heroin injectors from London in 1996, revealed that 50 per cent of them had stopped using opioids (this included seven non-users who had died from natural causes unrelated to addiction). Opioid addicts seeking assistance should be referred to drug dependence treatment units (DDUs) where staff are trained to deal with the problem and psychiatrists are licensed by the Home Office to prescribe the required treatment. The immediate aim of attending such a clinic is not necessarily withdrawal from opioids, but this can be achieved in one of three ways.

1. Without any support medication (’cold turkey’);
2. With support medication;
3. By substitution of another opioid for the abused substance and withdrawing this slowly.

Unsupported withdrawal usually only occurs when addicts decide to stop on their own initiative or if supplies of opioid are interrupted for any length of time, so forcing the addict into withdrawal (e.g. imprisonment, hospitalisation). The Department of Health recommends a variety of drugs that may provide symptomatic relief of some of the effects of withdrawal. These include propranolol, thioridazine and even benzodiazepines. However, a short course of clonidine is particularly useful for suppressing the signs of acute opioid withdrawal, although it does not prevent the more chronic symptoms which develop after the acute phase. Overactivity of central adrenergic neurones is thought to mediate many of the effects of withdrawal and this activity is suppressed by clonidine, a presynaptic alpha-2 adrenergic agonist which inhibits neurotransmitter release. Side effects may include sedation, dry mouth and hypotension. The latter side-effect makes it wise to monitor the patient after the first few doses. Clonidine is not licensed for this purpose , although the similar drug lofexidine is. Data on the efficacy of lofexidine are largely derived from open trials and no comparative studies involving the more widely used clonidine have been investigated include guanabenz and guanfacine. None of these drugs reduce craving for opioids, which is the most significant cause to recidivism.

A substitute can be prescribed to addicts in a dose sufficient to prevent withdrawal symptoms with one of two objectives. Prescribing daily maintenance doses may allow addicts to lead comparatively normal lives unperturbed by cravings for heroin, drug-seeking behaviour and all the concomitant unhealthy aspects of the street addict’s lifestyle. Some addicts may receive daily maintenance doses of medication indefinitely. Alternatively, the substitute may offer a convenient ‘bridge’ between an old drug culture lifestyle and the prospect of a drug-free existence. Once stabilised upon a suitable dose, patients can begin a structured withdrawal programme, involving gradual dosage reduction over weeks.

The substitute opioid most commonly used is methadone, usually as the elixir (1 mg/ml), but intravenous methadone can be made available for the few patients that find it difficult to abandon the injection habit. However, injection should be the exception rather than the rule and the number of prescriptions for methadone injection (estimated at over 9 per cent of the total) has been criticised. If the dose of opioid abused is not known, and for street heroin this is invariably the case, methadone must be titrated to symptoms of withdrawal. Methadone has a long half-life, allowing once daily administration may be needed initially.

Another advantage of the long half-life is that although withdrawal symptoms tend to be more sustain that those associated with heroin, they are milder; clonidine of lofexidine can be useful to further reduce severity. Signs of methadone withdrawal begin about 36-72 hours after last dose or dosage reduction. The duration of the withdrawal programme is highly variable and is best individualised according to the subject’s response and circumstances. It is probably better to reduce the quickly in the early stages, followed by a more prolonged series of reduction later. As mentioned above, complete detoxification may not be appropriate or desirable for all addicts.

It is important to realise that supply of methadone itself is not all that is required. If true social rehabilitation is to occur, full counselling and psychosocial support is necessary to prevent a return to old habits. Some addicts may use prescribed methadone to provide a baseline plasma level on which ‘top- ups’ of street drugs can be superimposed. Clearly this defeats the object of treatment. It can be identified by randome urine tests during clinic visits. Work in the USA suggests that prescribing larger doses of methadone may counteract this problem. Typically, USA, doses of 50 to 100 mg per day are used. These doses are believed to induce such a high level of opioid tolerance that ‘top-up’ doses of street heroin have no effects. However, in the presence of liver disease, consideration should be given to the use of low doses, as methadone is cleared hepatically. Ten deaths were reported from Australia in 1990 in patients with hepatitis who died within two to six days of starting an average of 60mg of methadone per day. It is possible that methadone accumulated to toxic levels.

Several clinics in England now supply heroin reefers in addition to, or instead of, oral methadone. These provide the ‘rush’ that addicts expect and seem to avoid the need for injections of street heroin. The Royal Pharmaceutical Society of Great Britain as developed a protocol giving guidance on the preparation of these reefers.

Methadone must be supplied with care, because it is clearly a substance that might itself be abused. The drug does appear on the street because addicts may swap their medication for other drugs of abuse or simply sell it. In addition, death may occur when non-tolerant individuals ingest this very potent drug. A single 50 to 100 mg dose of methadone can produce life-threatening effects in a new adult user and there have been a number of fatal accidental poisonings reported in the children of opioid-addicted parents.

Individuals maintained on methadone commonly require anti-depressants and laxatives as additional medication. It should be noted that recipients of regular maintenance doses of methadone may still genuinely require opioid analgesia. Since they are completely tolerant to the effects of methadone, analgesia should be prescribed in the usual way (i.e. on top of maintenance methadone), with due deference to the potential for abuse and the need to prevent constipation by prescribing laxatives.

Other opioids have been used as a maintenance treatment or to aid withdrawal. Most notable among these is levomethadyl acetate (LAAM), a potent opioid with a duration of action of some 72 hours. The long half-life of the parent drug and its metabolities allow administration three times weekly. The US Food and Drug Administration has approved levomethadyl as an alternative to methadone in treatment clinics. Other opioids which have been used include dextropropoxyphene and buprenorphine. The latter agent has partial agonist properties – it will give some rewarding opioid-like CNS effects but it may also antagonise the psychotropic effects of any heroin taken surreptitiously while on a treatment programme.

Naltrexone is an orally active opioid antagonist. Unlike buprenorphine, naltrexone has no agonist effects and antagonises the effect of opioids without the reward of an opioid ‘buzz’. This has severely limited the usefulness of the drug but it may be effective in preventing relapse in highly motivated people who have successfully negotiated acute opioid withdrawal because it not only prevents positive reinforcement but may diminish craving.

The experimental drug ibogaine may offer some hope to those dependent on opioids. It is claimed to halt the craving for opioids which occur in those who are attempting abstinence. There has been concern over the potential toxicity of ibogaine and some deaths have been reported. At the time of writing the only information on efficacy comes from animal studies and largely anecdotal human experiences. The drug is itself psychoactive and those who use it experiences. The drug is itself psychoactive and those who use it experience a 24- 36 hour ‘trip’ after one dose. Individuals are purported to emerge from the state free from opioid craving. In an open study of seven patients dependent upon heroin in 1994, three remained drug-free 14 weeks after completion of the study.

Designer Opioids

Fentanyl-based designer drugs are rarely seen in the UK but have been widely abused in the USA. As a group, the fentanyl-derived opioids are often sold under the name of ‘synthetic heroin‘. The most well-known example is alpha-methylfentanyl known the street as ‘China white‘; another example is 3-methylfentanyl (’3MF‘ or ‘TMF‘). These and other analogues can be over one thousand times more potent than heroin and have a short duration of action (typically 30 to 90 minutes). The two properties combined dramatically increase the positive reinforcement potential and therefore the risk of dependence occurring after only a few doses. They are usually injected but smoking or nasal inhalation is becoming more common. The drugs produce intense opioid effects with a very rapid onset and they can cause dramatic, sudden respiratory depression and death. Many deaths have been reported in the USA – in some cases death was so quick that abusers have been found with the needle still in situ. Unfortunately, fentanyl derivatives are not detected by routine immunoassay screening tests for opioids and so may not always be identified.

Pethidine analogues have also been reported from the USA – one in particular has come to the attention of the public: 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP). Several batches of illicitly produced MPPP were contaminated with MPTP, a very potent neurotoxin which caused irreversible brain damage with Parkinsonian-like symptoms.

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