Opioid use disorder

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

There is extensive evidence to support the combination of pharmacotherapies with psychosocial treatment for optimal management of opioid use disorders.[59][60] While detoxification primarily involves judicious use of medications, psychosocial support and supervision are also helpful at this stage. For longer-term treatment, pharmacological maintenance therapies with adjunctive evidence-based psychosocial treatments are effective in retaining patients in treatment and suppressing illicit opioid use.[61][62] Assessment of patient motivation for change, and evidence of family and social support, are important while planning treatment.

Non-specialists should consult and seek supervision from a practitioner experienced in treating addiction prior to prescribing pharmacotherapies to patients with opioid use disorders, particularly in special populations such as teenagers, pregnant women, and older adults. In older patients, it is important to assess for cognitive impairment or dementia as that can affect treatment, compliance, and aftercare. Current medications and herbal supplements should be completely reviewed to avoid potential interactions.[63] In addition, medication doses need to be adjusted based on a patient’s age, body mass index, renal function, liver function, and nutritional status (albumin). Safe storage of medications is crucial to prevent accidental or intentional overdose, particularly if there are children in the household.

The levels of service for the treatment of opioid use disorder should follow local guidelines to determine whether a patient is appropriate for early intervention, outpatient services, intensive outpatient services, partial hospitalisation services, residential services, inpatient services, or medically managed intensive inpatient services.[64]

Detoxification

Detoxification or withdrawal from opioids is necessary when a patient is physiologically dependent on opioids. It should not be considered as sufficient treatment in itself, but as the initial step in a long-term treatment plan to promote abstinence. Detoxification alone is associated with very high relapse rates unless followed by maintenance treatment. It can be performed in an outpatient or inpatient setting, depending on the severity of intoxication and withdrawal symptoms, presence of comorbid conditions, and safety issues.

Detoxification is accomplished using medication. Clinical trials have led to the development of semi-standardised protocols.[65] There are two evidence-based detoxification strategies: opioid agonist (i.e., methadone, buprenorphine with or without naloxone) substitution and taper, and use of an alpha-2 adrenergic agonist (i.e., clonidine or lofexidine) with or without naltrexone.[66][67] [ ] Methadone or buprenorphine (with or without naloxone) are first-line treatments for opioid detoxification.[66][68] Data from observational studies suggest that all cause mortality may be reduced by up to 50% among people with opioid dependence who are enrolled in any form of opioid agonist treatment.[69]

Clonidine and lofexidine (with or without naltrexone) are considered second-line agents.

Buprenorphine (with or without naloxone)

A first-line option for detoxification in adults.[66][68][70] Considered a highly potent partial agonist at the mu opioid receptor and an antagonist at the kappa opioid receptor.[71]
Available as a sublingual tablet containing buprenorphine only, or as a sublingual tablet or film containing buprenorphine and naloxone (a mu opioid receptor antagonist).
Buprenorphine/naloxone combination treatment was developed to deter parenteral misuse of buprenorphine.[72] When taken as sublingual tablets, buprenorphine’s opioid effects dominate and block opioid withdrawal.[72] If the sublingual tablets are crushed and injected, naloxone’s effects dominate and can precipitate withdrawal symptoms.[72]
Initiation of buprenorphine therapy differs from initiation of methadone in that buprenorphine therapy can precipitate withdrawal symptoms if given too soon after an opioid agonist.[41] Appearance of mild to moderate withdrawal symptoms should be observed before starting treatment.[41] Time to onset of withdrawal symptoms is dependent on the half-life of the opioid taken.[41] For example, heroin has a short half-life and is associated with withdrawal onset within 12 hours of last use, whereas withdrawal symptoms with methadone may manifest 24 to 74 hours after last use.[41]
It is unclear whether rapid reduction in the dose of buprenorphine is more effective than slow reduction and whether this depends on the context of withdrawal.[73]
Advantages: appropriate for home initiation, has a long duration of action, and withdrawal symptoms are relatively mild and less severe than those of methadone.[22][74][75][76] The effectiveness of buprenorphine is probably similar to tapered doses of methadone, but it is uncertain whether withdrawal symptoms resolve more quickly with buprenorphine.[73] Buprenorphine is superior to clonidine or lofexidine and comparable to methadone in terms of completion rates and withdrawal discomfort for opioid detoxification.[73] [ ]
Disadvantages: potential for misuse.[41]

Methadone

An alternative first-line option for detoxification in adults.[66][68][70] A pure, synthetic, orally administered, full mu opioid receptor agonist and N-methyl-D-aspartate (NMDA) antagonist that has been shown to be safe and effective for detoxification if used appropriately.[77]
There are two types of detoxification methods: a short-term (<30 days) detoxification for shorter-acting opioids, and a long-term (>180 days) detoxification for methadone-maintained patients.
It is best practice to wait for signs and symptoms of withdrawal to appear before starting methadone because of lack of certainty about physical dependence from unreliable histories and risk of overdose. If treatment is initiated prior to withdrawal signs and symptoms, vital signs and respiratory status should be carefully monitored.[41]
Induction is the most critical phase of treatment, and at this stage patients are 7 times more likely to die than untreated heroin addicts.[78] The induction phase lasts until the patient has been on a stable dose for 5 to 7 days.
Advantages: smoother taper than short-acting opioids (due to its longer half-life), and withdrawal symptoms are milder but prolonged compared with those of heroin.
Disadvantages: potential for misuse, possibly a longer taper than with buprenorphine or alpha-2-adrenergic agonists, requires closer monitoring than with buprenorphine due to longer half-life and risk for respiratory depression, and needs to be dispensed at a licensed clinic in the US.[22][41]

Clonidine or lofexidine (with or without naltrexone)

Alpha-2-adrenergic agonists (clonidine, lofexidine) reduce the sympathetic nervous system response (i.e., noradrenergic release) to opioid withdrawal. Lofexidine is a structural analogue of clonidine and is generally associated with fewer side effects.[41]
Usual doses of opioids should be given on the day prior to detoxification, with opioids discontinued abruptly the day clonidine or lofexidine is started.
Studies have found that addition of the opioid antagonist naltrexone to clonidine can shorten the duration of withdrawal without increasing discomfort.[79][80]
Lofexidine may not suppress withdrawal symptoms as fully as clonidine, and may therefore contribute to poorer treatment retention.[41]
Advantages: less potential for abuse, shorter treatment duration, and avoidance of long-term residual withdrawal symptoms that can occur with methadone.[41]
Disadvantages: medication adverse effects, higher dropout rate, and greater withdrawal discomfort (particularly hypotension and sedation) compared with opioid agonists.[41][81]

Supportive therapies

While there is no evidence of any specific nutrition or diet to aid detoxification, adequate hydration and food intake should be ensured.
Ancillary medications in therapeutic doses may be required for symptomatic relief, for example:[41]
- Ibuprofen for muscle cramps
- Bismuth subsalicylate, ondansetron, or prochlorperazine for gastrointestinal issues
- Trazodone for sleep disturbances.
Ondansetron should not be used as a first-line agent for treating vomiting in pregnant women owing to a possible increased risk of cleft palate with its use during the first trimester of pregnancy.[82][83][84]
Benzodiazepines may be given in an inpatient setting on a time-limited basis for treatment of anxiety or muscle cramps.[41] Monitoring for respiratory depression is required. Use caution if prescribing on an outpatient basis. Oxazepam and chlordiazepoxide are generally the benzodiazepines of choice in clinical practice.
Psychosocial counselling is primarily given during the maintenance phase; however, support and reassurance should be provided during detoxification, and it is desirable to develop adjunct psychosocial approaches that might make detoxification more effective.[85] [ ]

Stabilisation and maintenance

This stage is intended to promote abstinence from illicit drugs, prevent relapse, reduce HIV and hepatitis C risk, reduce mortality, and decrease criminality.[86][87] The goal is prevention or reduction of opioid withdrawal and craving, prevention of relapse, and restoration of functions disrupted by drug use. Continuing treatment after completion of detoxification is essential due to the high risk of relapse.

Although this phase can be accomplished without the use of opioid agonists, substantial evidence indicates that medication-assisted treatment is essential for a majority of patients with opioid use disorder.[88] Medications for relapse prevention include long-acting opioid agonists (i.e., methadone, buprenorphine) and opioid antagonists (i.e., injectable extended-release naltrexone). Treatment should be continued as long as the patient continues to benefit from treatment, wishes to remain in treatment, remains at risk for relapse, and suffers no serious adverse effects.

The choice of medication for maintenance treatment programme is determined by patient preferences, past history of response to treatment, and physician assessment of the short- and long-term effects of continued medication use.

Buprenorphine maintenance therapy (BMT) can reduce opioid abuse compared with placebo. However, a Cochrane review found that methadone maintenance therapy (MMT) at doses between 60 and 120 mg/day was more effective than BMT at both medium (8 to 15 mg/day) and high doses (16 mg/day) in retaining patients in treatment.[89] [ ] Both methadone and buprenorphine are associated with significantly lower all-cause mortality and overdose-related mortality when participants are on versus off treatment.[90]

Cross-sectional studies suggest that the rate of mortality with BMT may be lower than that with MMT.

Buprenorphine

A first-line option for maintenance therapy.[70][91][92][88]
Important properties that make it a good candidate for maintenance therapy include: less physical dependence and lower severity of withdrawal symptoms compared with methadone and heroin; due to a ceiling effect on respiratory depression and poor systemic bioavailability, it has reduced potential to produce lethal overdose, unlike methadone; and due to its prolonged duration of action (24 to 60 hours), it can be given once daily or even 3 times weekly.[93]
Available as a sublingual tablet containing buprenorphine only, or as a sublingual tablet or film containing buprenorphine and naloxone. Buprenorphine/naloxone combination treatment was developed to deter parenteral misuse of buprenorphine.[72] When taken as sublingual tablets, buprenorphine’s opioid effects dominate and block opioid withdrawal.[72] If the sublingual tablets are crushed and injected, naloxone’s effects dominate and can precipitate withdrawal symptoms.[72]
For patients stabilised on buprenorphine, it can be administered via a subdermal implant that delivers a consistent dosage of buprenorphine over 6 months. It can also be administered as a once-monthly injection for patients who have been on a stable dose of buprenorphine for a minimum of 7 days.[94] The US Food and Drug Administration has approved it for the treatment of moderate to severe opioid use disorder in adults who have initiated treatment with a transmucosal buprenorphine-containing product.
Can also be used to detoxify patients from methadone maintenance and transition to buprenorphine maintenance or a drug-free state.[95][96]
The first 4 weeks after cessation of treatment with buprenorphine is associated with a higher risk of death than in the remainder of time out of treatment, indicating a need during this time to focus clinical strategies in order to mitigate this risk.[90]

Methadone

A first-line option for maintenance therapy; may be preferred if both buprenorphine and methadone are equally suitable.[89][88][97] [ ] High oral systemic bioavailability and a long half-life make it an effective agent for maintenance.[91] Methadone may be associated with a lower risk of discontinuation than buprenorphine.[89][98]
Once a stable dose is reached after induction (based on suppression of craving and elimination of withdrawal), the maintenance phase begins. Patients have to come to the treatment programme daily for their methadone dosing and counselling. Patients who do well are permitted to take methadone home for unsupervised dosing. These guidelines allow up to 2 weeks supply after 1 year and 4 weeks supply after 2 years of treatment.
The first 4 weeks of treatment with methadone are associated with a higher risk of death (from all causes) compared with during the rest of treatment. This increase in mortality is reduced by persistent engagement with opioid substitution treatment and increased by dropping out of treatment, indicating a need to promote engagement with treatment during this initial 'golden' month.[90]
Methadone produces strong physical dependence. Discontinuation of methadone maintenance can lead to a protracted withdrawal syndrome that can last over 4 weeks. Only 10% to 20% of patients who discontinue methadone are able to remain abstinent.[65]
The first 4 weeks after cessation of treatment with methadone is associated with a higher risk of death than in the remainder of time out of treatment, indicating a need during this time to focus clinical strategies in order to mitigate this risk.[90]

Oral naltrexone

A pure mu opioid receptor antagonist that is non-addictive and produces no euphoria. Patient preference for naltrexone is low, because of its lack of agonist effects. This leads to poor medication compliance and low retention rates, which limits its use in the clinical setting. However, the development of longer-acting preparations of naltrexone may improve compliance as well as clinical efficacy.
Has been found effective in treating specific groups of highly motivated individuals such as nurses, physicians, and prisoners in release programmes.[99][100][101][102]
A systematic Cochrane review found no benefit of naltrexone over placebo or no treatment in retention, opioid abuse, or side effects.[103]
A naloxone challenge test could be considered prior to initiation of naltrexone maintenance therapy to evaluate level of opioid dependence.[46]

Parenteral naltrexone

An extended-release, parenteral formulation of naltrexone is available and is considered a useful treatment option due to the lack of risk of physical dependence.[70] In one trial, detoxified, opioid-dependent adults voluntarily seeking treatment who received this formulation had more opioid-free days compared with those who received placebo, and it was found to be generally well-tolerated.[104] Trials of extended-release injectable naltrexone show a consistent pattern of clinical efficacy for maintaining abstinence, achieving medication adherence, maintaining retention, protecting against re-establishment of opioid physical dependence, and possibly reducing craving for opioids for some individuals, while showing good safety and tolerability.[105][106]
The formulation can be used safely in patients with opioid use disorders, including those with underlying mild to moderate chronic hepatitis C virus and/or HIV infections, and is administered once monthly.[107]
When initiated, extended-release naltrexone has been shown to be as safe and effective as oral buprenorphine plus naloxone.[108][109]

Supportive therapies

Psychosocial interventions and urine drug screen monitoring, as well as assessment and treatment of comorbid medical and psychiatric conditions (e.g., depression, anxiety disorders, and personality disorders), should occur as a part of maintenance therapy.[110][111]
Psychosocial interventions are categorised into 'standard' and 'enhanced' care.[40] Standard care interventions offered by a key worker may include motivational interviewing, goal setting, recovery planning, and contingency management.[40] Enhanced care is offered if there is a poor response to standard care, or for patients with more complex needs.[40] This may include a residential rehabilitation programme with high-intensity cognitive behavioural therapy.[40] 12-step-oriented groups such as Narcotics Anonymous may also be beneficial.[112] UK Narcotics Anonymous Opens in new window
Pain self-management programmes based on the principles of mindfulness and cognitive behavioural therapy may support moderate reductions in opioid use.[113][114]
For drug use among parents, a Cochrane review found that psychosocial interventions addressing both parenting skills and substance misuse may have the greatest impact on abstinence (low-quality evidence).[115]
Monitoring of physical health problems (e.g., cardiovascular, respiratory, gastrointestinal), and HIV testing and counselling, as well as viral hepatitis screening and referral for treatment, should be integrated into a maintenance programme.

Adolescents

In general, young people need closer monitoring and regular supervision by adults. There are also issues of consent and confidentiality with teenagers that differ from adults. Family and/or parental involvement is crucial for the evaluation and treatment of adolescents. Prior to commencing pharmacological treatment, it is important to establish a safe environment for adolescents to rehabilitate. Experienced specialists should be the primary providers initiating treatments and supervising non-specialists in the continuation of treatment.

Regulations regarding whether an adolescent may obtain substance use disorder treatment without parental consent vary, and local guidelines should be followed.

The combination of buprenorphine with behavioural interventions is more efficacious in the treatment of opioid-dependent adolescents than the combination of clonidine and behavioural interventions.[116] However, further research is needed to evaluate the efficacy and safety of longer-term treatment with buprenorphine for opioid-addicted young people.[117][118]

Buprenorphine is generally preferred over methadone for induction and maintenance in adolescents because of its safety profile, except in instances of prior inadequate response to buprenorphine. It appears that adolescents with established opioid use disorder should be treated similarly to adults with respect to induction and longer-term stabilisation and maintenance with buprenorphine.

Methadone treatment is not usually given as a first-line treatment option in those under 18 years of age. In the US, methadone treatment in patients <18 years is allowed only if they have relapsed to opioid use after two documented attempts at detoxification or short-term rehabilitation.[119][120]

The usual supportive treatments should also be considered.

Pregnancy: antenatal management

Pregnant women with opioid use disorder experience increased obstetric and neonatal complications.[121] Detoxification is generally not recommended during pregnancy due to the risk of fetal distress and premature birth.[52][122][123] However, if absolutely necessary, opioid detoxification should be carried out in an inpatient setting.

Methadone and buprenorphine (with or without naloxone) are the drugs of choice for detoxification or maintenance therapy.[52][124] Methadone has not been associated with birth defects; however, it can lead to neonatal abstinence syndrome (NAS).[125] The American Academy of Pediatrics states that maternal use is compatible with breastfeeding. Women treated with a stable methadone dose before pregnancy may require dose adjustments, especially in the third trimester, although this is not required in all women and should be determined on an individual clinical basis. Rapid metabolism may develop in pregnancy, particularly in the third trimester, and in this scenario split (rather than daily) dosage may be best at controlling withdrawal symptoms (and may be associated with a reduced risk of neonatal abstinence syndrome).[52]

Buprenorphine with or without naloxone is a first-line alternative to methadone.[52][124] Buprenorphine monotherapy was previously recommended for pregnant women to avoid any potential antenatal exposure to naloxone.[52] However, studies evaluating buprenorphine in combination with naloxone have since found no adverse effects in pregnant women.[52] Buprenorphine appears to have a lower, but still significant, risk of NAS compared with methadone.[126][127][128] It also appears to result in improved birth weight due to longer gestation when compared with methadone treatment.[129] However, it should be noted that participants treated with buprenorphine in the study were required to present for daily dosing and received more intense psychosocial interventions than are typically offered in standard community care.[129] Multiple small case series have examined maternal buprenorphine concentrations in human milk. All concur that the amounts of buprenorphine in human milk are small and are unlikely to have short-term negative effects on the developing infant.[130]

A 2020 systematic review and meta-analysis found no significant differences in pregnancy outcomes between women receiving buprenorphine/naloxone compared with methadone or buprenorphine monotherapy.[131] Similarly, a Cochrane review published in the same year found methadone and buprenorphine to be comparable in efficacy and safety in pregnancy.[132]

Pregnant women receiving treatment with methadone should not transition to buprenorphine because of a significant risk of precipitating withdrawal.[52]

Data are insufficient to recommend initiation of naltrexone in pregnancy.[53] However, naltrexone may be continued in patients who are already on therapy and become pregnant after a careful assessment and risks/benefits discussion.[53]

Ancillary medications in therapeutic doses may be required for symptomatic relief. Treatments are generally the same as for non-pregnant women; however, certain drugs should be avoided or only used when the benefits outweigh the risks. Consult a specialist for further guidance on the selection of suitable supportive therapies in pregnant women.

Pregnancy: delivery and postnatal management

Acute pain management is challenging in this population due to fear among providers and patients of triggering a relapse, and the fact that patients often have a high tolerance to opioid analgesics.[53]

Women should be encouraged to have an epidural or combined spinal-epidural in early labour or as soon as contractions become uncomfortable.[53] Inhaled nitrous oxide should be avoided during delivery as it may be less effective in opioid-dependent women and is associated with increased sedation risk when taken concurrently with opioids.[53]

First-line treatment for postnatal pain is oral or intravenous paracetamol.[53] If pain persists for more than 24 hours, a full opioid agonist such as fentanyl or hydromorphone may be ordered.[53]

The American College of Obstetricians and Gynecologists recommends that, in general, breastfeeding should be encouraged in women who are stable on opioid agonist treatment, who are not using illicit drugs, and who have no other contraindications (e.g., HIV).[52]

Women with opioid use disorder may require additional antenatal care: for example, expanded STI testing and additional ultrasounds to assess fetal weight.[52] Babies born to mothers who used opioids during pregnancy (including methadone and buprenorphine) should be monitored after birth by a paediatrician for neonatal abstinence syndrome, which neonates may develop shortly after birth.[52]

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