Opioid misuse and dependence

Opioid is a broad term used to describe naturally occurring or synthetic substances that bind to opioid receptors.

Opioids are naturally occurring or synthetic substances that bind to opioid receptors. They may have agonist, partial agonist, or mixed agonist and antagonist activity at opioid receptors. An opiate is a natural derivative of the flowering opium poppy plant that has activity at opioid receptors. All opiates are opioids but not all opioids are opiates. In these notes we will use the term opioids of which there are several types:

• Naturally occurring opioids (i.e. opiates): codeine, morphine, and heroin.
• Synthetic opioids: fentanyl, methadone, and tramadol.
• Semi-synthetic opioids: buprenorphine, oxycodone, and hydrocodone.

Stimulation of opiate receptors causes pain relief, euphoria, sedation, respiratory depression and other features of opioid intoxication. Opioids are used to treat pain but are commonly abused because of their euphoric effects.

Opioid dependence

Opioid dependence is a chronic relapsing-remitting disorder that has negative physical, social and psychological consequences.

Opioid dependence develops after a period of regular use of opioids. The duration of use leading to physical and psychological dependence can be as little as 2-10 days. Key elements of opioid dependence include:

• Craving: a strong desire or compulsion to take opioids.
• Loss of control over opioid use.
• Tolerance: needing increasing amounts of opioid to produce the desired effect.
• Withdrawal: symptoms of withdrawal when opioid use is ceased or reduced.
• Opioid use takes priority: this means other important activities/interests are neglected.
• Persistent opioid use despite harmful consequences.

We advise that before reading these notes, you familiarise yourself with our note on Substance use disorders, which provides a broad overview. The following note details the pharmacology of opioids, the diagnosis of opioid use disorder, management of opioid overdose and withdrawal, opioid substitution therapy, and additional treatment considerations in this population including relapse prevention.

Different types of opioid receptors can be found within the body including kappa, delta, mu, and zeta.

There are 3 main opioid receptors found within the human body: Mu, Kappa, and Delta. Activation of these receptors shows overlapping functions. The Mu opioid receptors are the main target for the desired effects of illegal and prescribed opioids.

• Mu (µ): Main target for opioids. Effects include analgesia, euphoria, respiratory depression, miosis, constipation, and dependence.
• Kappa (k): Effects include Analgesia, sedation, diuresis, dysphoria/mood regulation, and miosis.
• Delta (δ): Effects include Analgesia, anxiolysis, and dependence.

Stimulation of µ-opioid receptors leads to dopamine release and the rewarding euphoric effects of opioids. These are thought to be largely responsible for driving the repeated use of opioids leading to dependence. Repeat opioid exposure leads to tolerance. In this physiological process, µ-opioid receptors are down-regulated and become less responsive to opioids, which in turn leads to less of a euphoric effect with opioid use.

With prolonged opioid use, there is also an up-regulation of the noradrenergic system to compensate for the sedating effects of opioids. When opioids are ceased, this up-regulation of the noradrenergic system is largely responsible for opioid withdrawal features.

Prescription opioid use is thought to have increased globally over the years.

Worldwide, opioid misuse is highest in the United States. In the UK, approximately 50% of people in contact with drug and alcohol services are being treated for opioid use. Approximately two-thirds of these people are 35-64 years old, with a median age of 42. Only 7% of people in treatment for opioid use were under 30 years old. Research suggests that a large proportion of opioid users now in treatment, started using heroin in the epidemics of the 1980s and 1990s and are now over 40 years old. In data collected in 2017-2018, 69% said they first used heroin before 2001 and only 9% first used heroin since 2011.

Overall, more males than females are in treatment for opioid dependence (males 70%, females 30%). Opioid use is strongly linked to social deprivation, with 56% of people in treatment for opioid use living in areas ranked in the 30% most deprived areas in England.

Multiple factors contribute to the increased risk of opioid misuse and dependence.

The major risk factors for opioid dependence include:

• Chronic pain and long-term prescription of opioids: long-term use of opioids may lead to tolerance and the need for increasing doses. Those who are not prescribed higher doses may resort to obtaining opioids illegally, increasing the risk of misuse.
• Psychiatric co-morbidities (e.g. depression, anxiety, PTSD, psychosis): the euphoric effects of opioids can temporarily reduce the symptoms of anxiety/depression and opioids may be used in an attempt to self-medicate these symptoms.
• Other substance misuse: a history of alcohol or other substance misuse and previous contact with drug and alcohol services.
• Family history of substance misuse.
• Personality traits: including disinhibition, poor impulse control, novelty, or sensation seeking. These may all increase the risk of opioid misuse and dependence.
• Social factors: unemployment, social deprivation, regular contact with those who use drugs, and history of criminal activity.
• Adverse / stressful life events: may trigger initial substance misuse or a relapse (e.g. abuse, bereavement, job loss).

The diagnosis of Opioid Use Disorder is based on the DSM-V criteria.

The formal diagnosis of Opioid dependence is known as 'Opioid Use Disorder' and can be made using the DSM-V criteria, which are outlined below.

Opioid Use Disorder describes a problematic pattern of opioid use leading to clinically significant impairment or distress, and at least two of the following should be present that have occurred within a 12-month period:

1. Increased consumption: opioids are often taken in larger amounts or over longer periods than intended.
2. Loss of control: persistent desire or unsuccessful efforts to cut down or control opioid use.
3. Time-consuming: a lot of time spent in activities necessary to obtain opioids, use opioids or recover from their effects.
4. Craving: a strong desire or urge to use opioids.
5. Not fulfilling responsibilities: recurrent opioid use that causes a failure to fulfill major role obligations at work, school, or home.
6. Continued opioid use despite negative effects on social or interpersonal problems: these problems are likely to have been caused or exacerbated by the effects of opioids.
7. Opioid use takes priority over other activities: important social, occupational, or recreational activities are given up or reduced because of opioid use.
8. Recurrent opioid misuse in situations in which it is physically hazardous.
9. Continued opioid use despite negative effects on physical or mental health.
10. Tolerance: a need for increased amounts of opioids to achieve the desired effect or diminished effects with continued use of the same amount of an opioid.
11. Withdrawal symptoms: development of symptoms upon ceasing opioid use, or avoiding the effects of withdrawal by continuing to use opioids.

The management of opioid dependence and misuse can be complex and depends on the presentation (e.g. overdose, withdrawal, chronic use).

The management of opioid dependence can be divided into:

1. Management of opioid overdose
2. Management of opioid withdrawal
3. Opioid substitution therapy
4. Opioid relapse prevention
5. Managing the physical health complications of opioid misuse
6. Other management considerations in opioid misuse

For a detailed discussion on each of these areas, see the topic subsections below.

Opioid overdose from acute intoxication can lead to life-threatening respiratory depression resulting in coma and death.

Clinical features of opioid intoxication include initial euphoria often followed by apathy, sedation, pupil constriction, itching, hypotension, bradycardia, and reduced respiratory rate. The key clinical features of opioid overdose are unconsciousness, low respiratory rate, and pinpoint pupils. In severe cases, opioid overdose can lead to coma and death.

Opioid overdose is treated with naloxone; an opioid antagonist targeting all opioid receptors. The individual with an opioid overdose will require close monitoring in a clinical setting. Repeated doses of naloxone are often required in those who have taken a long-acting opioid due to naloxone’s short half-life (30-120 mins). Depending on the circumstances, a naloxone infusion may be required rather than repeated bolus doses. Administration of naloxone may precipitate opioid withdrawal features which are unpleasant but not usually dangerous.

Opioid withdrawal may be spontaneous (cessation or dramatic reduction in use) or precipitated (administration of naloxone).

Spontaneous opioid withdrawal follows cessation or dramatic reduction in opioid use. Precipitated opioid withdrawal follows administration of an antagonist (e.g. naloxone or naltrexone).

The timing of withdrawal will vary depending on the half-life of the opioid taken. For example, heroin withdrawal occurs within 4-6 hours of the last heroin use, peaks at 48 hours, and subsides within 5 days. Methadone withdrawal peaks at 5 days and subsides within 10 days. Buprenorphine withdrawal can last 10 days.

Clinical features of opioid withdrawal are mediated by noradrenaline overactivity and include:

• Dilated pupils.
• Cardiovascular: tachycardia, hypertension.
• Neuropsychiatric: insomnia, restlessness, anxiety, irritability, tremor, and shivering.
• Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhoea.
• Other: watering eyes, rhinorrhoea, yawning, sneezing, goosebumps, muscle aches, and excessive sweating.

Although unpleasant, heroin withdrawal is not generally dangerous (except in pregnancy).

Lofexidine is an alpha-2 adrenergic receptor agonist. It inhibits the release of noradrenaline in the central and peripheral nervous system, thereby reducing opioid withdrawal symptoms that are driven by noradrenaline overactivity

Other supportive management of opioid withdrawal symptoms focuses on alleviating the symptoms:

• Diarrhoea: consider loperamide and ensure to maintain good hydration.
• Nausea/vomiting: consider the need for anti-emetics such as metoclopramide.
• Agitation, anxiety or insomnia: consider the need for a short-term prescription of a benzodiazepine or a sleeping tablet e.g. zopiclone.
• Muscle pains: may be helped with simple over-the-counter analgesia such as paracetamol or ibuprofen.

Opioid substitution therapy (OST) can be used in those who are opioid dependent for maintenance or detoxification.

Opioid substitution therapy (OST) can be part of opioid maintenance therapy or opioid detoxification:

• Opioid maintenance therapy: aims for harm reduction and stabilisation of lifestyle. It provides a regular opportunity for Drug and Alcohol Services to engage with the opioid user, enables their social needs to be assessed, and social support implemented. It can also promote the reduction of illicit drug use and allows for the identification and treatment of co-morbid physical or mental health problems. Maintenance therapy is suitable for people who wish to stop or reduce opioid consumption but don’t feel able to completely abstain from opioids.
• Opioid detoxification: aims for safe and effective cessation of opioids whilst minimising withdrawal symptoms. This might be suitable for motivated individuals, who have good social support and otherwise stable life circumstances. Outpatient opioid detoxification usually takes place over 12 weeks (28 days as inpatient). OST can be given alongside lofexidine for the management of withdrawal symptoms. Individuals need to be aware that after detoxification, there is a loss of opioid tolerance and an increased risk of overdose and death from future opioid use.

Opioid substitution therapy choice

The two opioids used in OST are methadone and buprenorphine. The choice between methadone and buprenorphine is made on an individual basis taking into account multiple factors including the risks and benefits of each treatment, likelihood of diversion, individual preference, and previous positive or negative experiences with either drug.

Methadone is a Schedule 2 Controlled Drug (CD) and buprenorphine is a Schedule 3 CD. There are legal requirements for writing Controlled Drug prescriptions which include:

• The patient's full name, date of birth and address.
• The form and strength of preparation.
• The dose to be taken.
• The daily dose amount and total amount should be prescribed in both numbers and words.
• Signature of prescriber and the date.

No more than one week’s supply should be dispensed at one time.

Methadone

Methadone is a synthetic opioid, which works as a full agonist at the Mu opioid receptor.

• Form: oral solution
• Peak concentration: 4 hours
• Half-life: single dose (15 hours), regular daily dosing (37 hours)
• Withdrawal symptoms: severe
• Monitoring: daily supervision for at least 3 months. Liver function tests 6-9 monthly (metabolised by the liver)
• Risk of overdose: high. The relatively slow onset of action and long half-life means that methadone overdose may only fully manifest and become life-threatening several hours after the dose is taken. There is also a risk of arrhythmias due to QTc prolongation and a higher risk of respiratory depression compared to buprenorphine.
• Risk of diversion: lower. There is generally a low risk of diversion as it is a supervised oral solution. Tablets can be crushed and injected so not usually prescribed.

Methadone should be started at a low dose and slowly up-titrated. It may take 4-5 days for plasma levels to stabilise. Repeated dosing leads to accumulation and therefore methadone initiation should be done cautiously and gradually over a few weeks to reach therapeutic range. There is an increased risk of mortality in the titration phase.

Buprenorphine

Buprenorphine is a semi-synthetic opioid, which works as a partial agonist at the Mu opioid receptor (leads to less euphoric effects and blocks the action of other opioids).

• Form: sublingual tablet (Subutex = buprenorphine / Suboxone = buprenorphine and naloxone)
• Peak concentration: 2 hours
• Half-life: 24-42 hours
• Withdrawal symptoms: Milder
• Monitoring: daily supervision for at least 3 months. Liver function tests 6-9 monthly (metabolised by the liver)
• Risk of overdose: lower.
• Risk of diversion: higher. Sublingual buprenorphine can be more easily diverted and there is a risk of tablets being crushed and injected. Buprenorphine is available in combination with naloxone to reduce this risk (suboxone). Suboxone combines buprenorphine and naloxone in a 4:1 ratio. When taken sublingually naloxone has a very low bioavailability and doesn’t diminish the therapeutic effect of buprenorphine. However, if injected naloxone has high bioavailability and can precipitate withdrawal. This discourages diversion and misuse by injection.

Buprenorphine blocks the effects of additional opioid use by occupying opioid receptors. This leads to less euphoric effects and due to the longer half-life and less severe withdrawal features, it may be a better option for opioid detoxification. There is a risk of precipitating opioid withdrawal due to the high affinity for the µ-opioid receptors. Buprenorphine can displace full agonists and precipitate withdrawal when treatment is initiated. Therefore, buprenorphine usually starts when a person begins to experience opioid withdrawal.

Dose titration can occur slightly faster than with methadone. A therapeutic dose can be reached over a few days with no increased risk of mortality.

Drug interactions

Both drugs are metabolised in the liver via the cytochrome P450 enzymes (CYP3A4 enzyme). This means drugs that interact with the P450 enzymes can alter the concentration of these drugs.

• P450 enzyme inhibitors (fluconazole, anti-retroviral medication, erythromycin): increase blood levels of methadone and buprenorphine
• P450 enzyme inducers (e.g. rifampicin, phenytoin, carbamazepine): decrease blood levels of methadone and buprenorphine

With both drugs, there is an increased risk of respiratory depression and sedation with concurrent alcohol and benzodiazepine use. There also needs to be caution with other drugs that cause QT interval prolongation due to the increased risk of ventricular arrhythmias (e.g. citalopram, amiodarone, antipsychotics).

Naltrexone can be used as part of opioid relapse prevention.

Naltrexone is a competitive antagonist of µ-opioid receptors, that also has action at other opioid receptors. It can be used to aid opioid abstinence in individuals who are highly motivated with good social support and can aid medication compliance. The minimum recommended interval between opioid cessation and commencing naltrexone depends on the half-life of the opioid used, the duration of use, and the amount taken at the last dose. This interval is usually at least 7-10 days, otherwise, there is a high risk of precipitating opioid withdrawal. Individuals need to be aware that after abstinence from opioids, there is a loss of opioid tolerance and an increased risk of overdose and death from future opioid use.

Needle and syringe exchange programmes are promoted as a harm reduction strategy to reduce and prevent physical health issues related to unsafe injection practices.

Physical health complications secondary to injecting opioids can include:

• Infection: introduced into the body by unsterile injection practices. Common pathogens include Staphylococcus aureus or Group A Streptococci. Infections can be localised to the injection site (skin/soft tissue infection, abscess) or spread systemically (e.g. bacterial endocarditis, osteomyelitis, sepsis).
• Blood-borne viruses: HIV, hepatitis B, and hepatitis C.
• Deep vein thrombosis and pulmonary emboli: injecting drugs increases the risk of superficial thrombophlebitis due to repetitive trauma, unsterilised techniques, and irritation caused by drug mixtures. Individuals who inject drugs are at a substantially higher risk of developing a DVT.
• Other lower limb complications: the veins in the groin are commonly used sites for drug injection. This can lead to leg ulcers, varicose veins, and chronic leg swelling.

Needle and syringe exchange programmes are promoted as a harm reduction strategy to reduce and prevent physical health issues related to unsafe injection practices. It provides users with access to sterile needles, syringes, and other equipment. It also provides a means for safe disposal of used needles and syringes.

General poor health and self-neglect are common among those with opioid dependence. Poor nutrition, weight loss, and dental disease is also common.

Harm minimisation is a key concept in the management of substance misuse.

Where drug abstinence is not possible, practices are implemented that aim to reduce the harm associated with drug use. This is known as harm minimisation. These include the previously detailed opioid substitution therapy and needle syringe exchange programmes. Harm minimisation is also attained by regular contact with community drug services, helping the individual deal with drug-related problems and encouraging health-related behaviours.

Ultimately, the management of substance misuse, abuse, and dependence is complex and involves a full multidisciplinary approach. Please see our note on Substance use disorders for further information about the general management principles of substance misuse.

Opioid dependence is a chronic relapsing-remitting disorder with high relapse rates.

There is a worse prognosis in those with coexisting conditions such as mental health problems or cognitive impairment. Opioid dependence is associated with high morbidity and mortality. Mortality rates are estimated at 10-20 times greater than the general population. The main causes of drug-related deaths are overdose, suicide, violence, accidents, and physical health complications of drug misuse.

Last updated: January 2024

References:

DSM-V

Adult substance misuse treatment statistics 2020 to 2021: report - GOV.UK (www.gov.uk)