Definition And Clinical Consequences Of Opioid Dependence

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"A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use that typically include a strong desire to take the drug, difficulties in controlling its use, persisiting in its use despite harmful consequences, a higher priority given to drug use then to other activities and obligations, increased tolerance and sometimes a physical withdrawal state".a

The term opioid covers a range of psychoactive chemicals derived from the poppy plant, Papaver somniferum (such as opium and morphine) and semi-synthetic compound (heroin/diamorphine) as well as synthetic ones (methadone, buprenorphine and pethidine).a,b Opioids are use in the medicine field primarily for its analgesic properties but misuse by the general population for its euphoric properties does occur. It is estimated that 15.6 million people in this world are illicit opioid users, with 11 million people on heroin itself. Regular misuse of opioid eventually leads to development of opioid dependence, although regular use itself might not be the sole reason. It is now widely accepted that opioid dependence is a medical disorder of the brain which occurs due to neurological changes as a result of regular misuse.a Misuse of opioid repeatedly results in tolerance. Due to development of tolerance, opioid misusers eventually move on to higher doses of the opioid and subsequently start to inject the opioid straight into their veins for a faster and greater effect. In the United Kingdom (UK), an individual who uses opioid and/or crack cocaine can be defined as a problem drug user (PDU). The UK Focal Point 2010 report estimated that there are a total of 397,346 PDUs in the UK, at a rate of 9.79 per 1,000 population aged 16 to 64. These PDUs are mostly polydrug users, with at least 262,468 opiate users in England itself. The latest estimation on injecting PDUs was 147,900 in the year 2009, at a rate of 3.69 per 1,000 population aged 16 to 64.c

Opioid misuse has been associated with various health and social harms. Mortality of an opioid misuser is high, ranging from 12 to 22 times to that of a non-drug using peer.a A 2010 annual report by the national report on Substance Abuse Deaths (np-SAD) reported a total of 2,182 drug-related deaths occurring in the UK in 2009. Overdose was reported as the main cause of death (72.3%). Opioid alone or in combination with other substances were implicated in the majority of the deaths.e Opioid users that inject face a greater risk of blood-born viral infections such as Human Immunodeficiency virus (HIV) infection, hepatitis infection and bacterial infection due to their injecting habits and needle sharing. The prevalence of HIV infection among injecting opioid users has been on the rise for the past decade from 0.7% to 1.5%, a level similar to the 1990s.a In the year 2009, a total of 11,005 cases of Hepatitis C was diagnosed in the UK and 90% of these infections were due to injecting practices. Approximately half of the injecting drug users in the UK have tested positive for hepatitis C antibody. Hepatitis B infections have declined over the years but it is still prevalent in about 16% of injecting drug users.d Such infections will eventually lead to long-term complications such as liver failure. In injecting drug users, bacterial infection, leading to abscess, sore of open wound commonly occurs at the injection sites. In the year 2009, 22 cases of wound botulism, 1 case of tetanus, 14 cases of streptococci infection, and 27 cases of meticillin-resistant Staphylococcus Aureus (MRSA) infection were reported in injecting drug users. From the year 2009 up to 2010, 51 cases of Anthrax infections were reported, though this is a consequences of a contaminated batch of opioid more than the injecting habits of drug users.d

Individuals who are opioid dependent experience a significant reduction in their quality of life due to their drug-seeking behavior and replacement of meaningful activities by time spent intoxicated. Social problems such as poor parenting, unemployment, homelessness and crime can result from the use of illicit drugs.a Records obtained from clients entering treatment in the UK in 2008/09 showed that only about 15% of them have a regular employment.c Drug-seeking behavior will also entice individuals to commit crime to obtain funds for their addiction.

Besides that, opioid misusers have a higher risk of psychiatric comorbidity.a,c

Treatment Options

There are currently 4 drugs which are licensed for the treatment of opioid dependence in the UK. They are methadone (opioid agonist). Buprenorphine (partial opioid agonist), lofexidine [alpha2 (α2)-adrenoceptor agonist] and naltrexone (opioid antagonist).b,f

Methadone is a long-acting synthetic opioid agonist with similar pharmacological activity as the natural product, morphine.g Methadone acts on the µ-opioid receptor to prevent withdrawal symptoms but does not deliver the intense euphoric 'high' associated with heroin, possibly due to its slow onset of action.a,b It does, however provides some mild opioid reinforcing effects.g Initial dosing is 10-40mg daily, depending on the patient's normal opioid usage (tolerance).f,h If the tolerance is low or uncertain, it will be more appropriate to start at a lower dose of 10-20mg.h The dose of methadone can be increased by up to 10mg daily until there is absence of withdrawal symptoms. However, there is a maximal increase limit of 30mg per week. The usual dose range is 60-120mg daily.f Oral methadone has a high bioavailability of approximately 85%.a Long elimination half-life of approximately 20 to 37 hours allows once daily dosing.h The drug is metabolised by the hepatic enzyme cytochrome P450, primarily the CYP450 3A4 enzyme. Therefore, care has to be taken if the patient is on medications which interfere with the enzyme. Due to the high prevalence of viral infections among opioid users, it would be common for patients to be on antivirals. Methadone has been shown to exhibit drug-drug interaction with certain antivirals, particularly protease inhibitors and non-nucleoside reverse transcriptase inhibitor (NNRTI). It is possible for protease inhibitors to decrease the metabolism of methadone, leading to toxicity. NNRTIs on the other hand, increase the metabolism of methadone, resulting in treatment failure due to subtherapeutic doses of methadone .i During the induction period, Methadone has been associated with a high risk of death due to respiratory depression.a,b, h,j A study by Zador & Sunjic (n=238) found that 21% of the subjects died during the first week of their Methadone Maintenance Therapy (MMT), with majority of the death (88%) being drug-related. The authors concluded that the deaths were due to inadequate assessment of the patient's tolerance to methadone and the use of other Central Nervous System (CNS) depressants by the patients themselves.k Therefore, it is extremely important for patients, who are on methadone to avoid respiratory depressants such as other opioids, alcohol, sedatives (benzodiazepines), and antidepressants.b At the same time, the slow onset of action of methadone means any toxic effects might present itself several hours after administration.j With methadone, there is also an increase risk of life-threatening cardiac arrhythmias due to the slight prolongation of QT interval in certain patients who are taking methadone.a,h For the treatment of opioid dependence, the medication is available in the form of oral solution 1mg/ml (£1.27 for 100ml) & 5mg/ml (£1.47 for 20ml), oral concentrate (Methadose®) 10mg/ml (£12.01 for 150ml) & 20mg/ml (£24.02 for 150ml) and injection 25mg/ml (£2.05 for 2ml ampoule) & 50mg/ml (£2.05 for 1ml ampoule).f The prices are exclusive of VAT.

Buprenorphine is a long-acting synthetic partial opioid agonist at the µ-opioid receptor. It occupies the receptor without fully activating the system.b Buprenorphine is administered through the sublingual route at an initial single dose of 0.8-4mg daily. The dose would then be increased according to response up to a maximum of 32mg daily.f Similar to methadone, buprenorphine is also metabolized by the enzyme CYP450 3A4. However, the same study which compares interaction between methadone and antivirals found that unlike methadone, buprenorphine dosing is not affected by co-administration of the NNRT efavirenz. The authors concluded that this is due to buprenorphine being metabolised to and active metabolite whereas methadone is metabolised to an inactive metabolite.i When compared to methadone, buprenorphine is deem a safer drug due to the fact that it is not a full opioid agonist and therefore, a lower risk of overdose and respiratory depression.a,g,h,j A study by Walsh et al had shown that buprenorphine exhibits ceiling effects. The maximal respiratory depression was obtained at a dose of 16mg and was still tolerable by the subject.k Though buprenorphine carries a low risk of respiratory depression compared to other opioids, concurrent use with other respiratory depressant such as those mentioned for methadone should be avoided or initiated with caution.f Buprenorphine also has a higher affinity for the µ-opioid receptors and a slower dissociation from the receptors compared to heroin and methadone. This prevents any additional illicit opioid which a patient might have taken after a dose of buprenorphine from exerting any effects on the patient.g,j However, as buprenorphine is also a partial antagonist, it will precipitate withdrawal symptoms in patients on high daily opioid doses.b Therefore, the opioid doses in these patients should be gradually reduced before buprenorphine is intiated. Besides that, it is advisable to administer the first dose of buprenorphine upon presence of withdrawal signs from any opioid-dependent patient or approximately 6-12 hours after the patient has last taken any short-acting opioid. If the patient uses long-acting opioid, a waiting period of 24-48 hours might be required.f For the treatment of opioid dependence, the medication is available in the form of a sublingual tablet of 0.4mg (£1.57), 2mg (£7.74), and 8mg (£20.54) in a 7-tablet pack.f Prices are exclusive of VAT.

Lofexidine is an α2-adrenoceptor agonist which acts on α2-adrenoceptors in the peripheral and central nervous system. As a result, there is a reduction in the release of endogenous adrenaline and noradrenaline. Excess of these neurotransmitters has been implicated in the adrenergic component of opioid withdrawal, such as runny nose, wet eyes, sweating and shivering.a,b The initial dose of lofexidine is 0.8mg daily in divided doses. The dose can be increased by 0.4-0.8mg daily to a maximum of 2.4mg daily in divided doses, with a maximum single dose of 0.8mg. Since lofexidine is not an opioid, there will not be any risk of respiratory depressant. However, lofexidine does not alleviate non-adrenergic withdrawal symptoms such as diarrhea, nausea&vomiting, stomach cramps, headaches, anxiety, agitation and muscle pains.b Other adjuvants will be required to address these symptoms. Clonidine, also an α2-adrenoceptor agonist is not licensed for treatment of opioid dependence in the UK but is used in a minority of cases. Compared to lofexidine, clonidine has a much more severe adverse effect of hypotension.b Lofexidine is available in the form of 0.2mg tablet and is marketed in the UK under the trade name BritLofex® at a price of £61.79 for a 60 tablets pack, exculsive of VAT.f

Naltrexone is a long-acting opioid antagonist with high affinity for µ-opioid receptors. As an antagonist, naltrexone does not activate the receptors.g Occupation of the µ-opioid receptors will prevent any effects from future administration of opioid agonist. In opioid-dependent patients, it will displace the opioids from the receptors and lead to abrupt precipitation of withdrawal symptoms.b Naltrexone displaces methadone and heroin in a time frame of minutes whereas buprenorphine in a time frame of 1 to 4 hours.a The initial dosing of naltrexone is 25mg on day 1, which is eventually increased to 50mg daily therafter.f,m The medication is available in the tablet form and is marketed in the UK under 2 trade names, namely Nalorex® and Opizone® at the price of £22.34 and £23.00, respectively for a 28 tablets pack, exculsive of VAT.

In general, treatment of opioid dependence can be done through two different pharmacological approaches, namely maintenance therapy and detoxification therapy. There is also a non-pharmacological approach known as psychosocial intervention, which is often used concurrently with pharmacological approaches.

Maintenance therapy involves a daily administration of an opioid agonist (methadone) or partial opioid agonist (buprenorphine) to an opioid dependent patient to enable the patient to live a normal active life in the absence of any withdrawal symptoms or urge to use illicit opioids.a,n The aim would be to reduce or cease the use of illicit opioids, prevent transmission of blood-born virus, reduce the risk of overdose, reduce crime rate and improve the social as well as overall health of the patient.a The Cochrane Collaboration published a systemic review and meta-analysis of methadone maintenance therapy (MMT) vs. no opioid replacement therapy for opioid dependence in the year 2009. The outcomes that were evaluated were mortality (4 studies), retention in treatment (7 studies), abstinence from heroin (6 studies) and criminal activity (3 studies). Meta-analysis of the 4 studies that evaluate mortality shows that methadone reduces mortality in the treatment group (n=576; RR=0.48, 95%CI: 0.10-2.39). However, this result is not statistically significant (p=0.37). Studies which evaluate retention in treatment were divided into 3 old (before year 2000) and 4 new (after year 2000) studies. All studies show that methadone is effective in treatment retention. Results from the new studies (n=750; RR=4.44, 95% CI: 3.26-6.04) show a greater superiority methadone compared to the old ones (n=505; RR=3.05, 95% CI: 1.75-5.35), at a highly significant p-value of <0.00001 and 0.000092, respectively. Results from studies which evaluate heroin abstinence show that methadone has an significant (p<0.00001) advantage over non-treatment groups (n=1129; RR=0.66 95% CI: 0.56-0.78). The pooled result from the 3 studies shows that MMT is effective in reducing criminal activities (n=363; RR=0.39, 95% CI: 0.12-1.25), though this result is not statistically significant (p=0.11).o The use of buprenorphine in maintenance therapy has also been reviewed by The Cochrane Collabration. A systemic review and meta-analysis of buprenorphine maintenance therapy (BMT) vs no opioid maintenance therapy or MMT was published in 2008. Buprenorphine in 3 different doses: low, medium and high shows

Buprenorphine dose was classified to 3 different categories: low (2-6mg), medium (), highWhen compared to the non-treatment group,

Matrick et al conducted a meta-analysis on methadone maintenance therapy vs no methadone maintenance therapy.

Amato et al conducted a meta analysis

Methadone vs placebo

-mortality, retention, crime

Methadone dose

Buprenorphine vs placebo

-mortality, retention, crime

Buprenorphine dose

Methadone vs buprenorphine

Heroin use?

Maintenance vs placebo



Maintenance vs withdrawal

Look up suitable methadone dose in literature - move to MMT

Compare mortality of methadone vs buprenorphine? - move to MMT

Look up suitable dose in literature (buprenorphine)

Compare methadone to buprenorphine during induction period -take someinfo from NICE p.82

Psychosocial intervention

Economic cost for drug vs drug

Economic cost of maintenance vs withdrawal (detoxification)

Treatment Recommendation