Opioids and Opioid Use Disorder: General Considerations

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the term “opioid-induced disorders” (intoxication and withdrawal), whereas both terms “abuse” and “dependence” are encompassed by “opioid use disorder,” which is used synonymously with the term “addiction.” However, the terms “abuse,” “dependence,” and “addiction” are still used often and sometimes interchangeably.

Opioids are a powerful class of medications that are frequently used for the treatment of acute and chronic pain. Chronic use of any opioid can lead to physical and psychological dependence, and rapid cessation or dose decreases can lead to symptoms of opioid withdrawal. Also see Pain Management: Basic Principles.

Opioid use disorder (OUD) is a condition that can develop in those accessing prescription medications, street supply, or both. When taking history, the 4 C’s should be considered:

1) Compulsion: A preoccupation with finding and using opioids.

2) Cravings: An increase in opioid use due to cravings.

3) Consequences: Continued opioid use despite negative personal, social, professional, financial, legal, or other problems.

4) Control: Loss of control, unsuccessful attempts to restrict opioid use, negative personal and social consequences of opioid use.

Of note, tolerance and withdrawal alone do not constitute OUD, as this is a physical effect of taking certain medications over time.

OUD is used synonymously with opioid addiction. Opioid addiction refers to the psychological dependence in OUD. Addiction is the emotional connection to the perceived effects of a substance, which may remain even once the physical dependence to opioids is removed.

The precise criteria of mild, moderate, and severe OUD can be found in the DSM-5; an overview is available online from the British Columbia Centre on Substance Use.

DefinitionsTop

Opiate, also known as opioid alkaloid, is a natural chemical found in opioid plants (eg, morphine, codeine, papaverine).

Opioids include any natural, semisynthetic, or synthetic substance that binds to opioid receptors and produces similar narcotic effects (eg, sedation, pain relief, slowed breathing, and euphoria).

Endogenous opioids are neurotransmitters naturally created by and circulated within the body (ie, endorphins, enkephalins, dynorphins).

Semisynthetic opioids are chemically modified opioids (eg, heroin, oxycodone, hydrocodone, hydromorphone, oxymorphone).

Synthetic opioids are created opioids (eg, methadone, fentanyl, meperidine [INN pethidine], tramadol, loperamide, diphenoxylate).

Opioid agonist therapy (OAT) refers to use of prescribed medication-based therapy with long-acting opioids (eg, buprenorphine, methadone, sustained-release morphine) to help with the management of withdrawal symptoms and in the treatment of OUD.

OpioidsTop

The provided trade (brand) names are valid for Canada.

1. Morphine is the main alkaloid of opium, the milky fluid from unripe poppy seeds. The fluid is extracted to obtain a white powder. Slow-release oral morphine (SROM) (brand name Kadian) is a 24-hour time-release formulation (distinct from sustained-release morphine given every 12 hours) that has been used as third-line OAT in the treatment of OUD. SROM can be used as an alternative OAT (see Opioid Agonist Therapy, below) in patients who are intolerant of or have contraindications to buprenorphine and methadone.

2. Oxycodone is a semisynthetic opioid used primarily as a prescription medication for either immediate-release or extended-release formulations. Oxycodone is marketed for the treatment of moderate to severe pain and has been used recreationally through oral, insufflated, or injected routes. It was originally available as a stand-alone formulation or formulated together with acetaminophen (INN paracetamol) or acetylsalicylic acid (ASA). Newer formulations have made it difficult to crush or dissolve the medication.

3. Hydromorphone (brand name Dilaudid) is a semisynthetic opioid marketed for the treatment of moderate to severe pain. It is available in immediate-release or extended-release formulations and can be administered orally, subcutaneously, IM, or IV. When used recreationally, hydromorphone may be taken orally, insufflated, or injected. There is some evidence that injection of crushed controlled-release hydromorphone tablets leads to a high risk of infectious complications.

4. Tramadol is a synthetic opioid and weak agonist of opioid receptors as well as a reuptake inhibitor of serotonin and norepinephrine. Tramadol may be metabolized differently by individuals with the same tolerance. Therefore, clinical manifestations following ingestion of the same dose may vary from person to person.

5. Heroin (diacetylmorphine, diamorphine) is a semisynthetic opioid that is most frequently taken recreationally. Heroin can be injected (IV, subcutaneously, or IM), snorted as powder, or inhaled/smoked after being heated on a metal foil. When mixed with other psychoactive substances (eg, cocaine and amphetamine), it is referred to as “speedball.” When used IV, it immediately produces a short-lasting effect (1-2 minutes) but strong euphoria, which is followed by ~1 hour of sedation and 3 to 5 hours of analgesic effect. Intranasal or IM administration produces a euphoric effect after 15 to 30 minutes. Heroin is metabolized by the liver to morphine and codeine, which are then excreted by the kidneys.

6. Fentanyl is a synthetic opioid and strong selective mu-opioid receptor agonist commonly used in the hospital setting for severe pain and anesthesia. Illicit fentanyl is increasingly available as a street drug, either in isolation or mixed with other drugs (heroin, cocaine), which has led to a significant spike in overdose deaths.

Fentanyl is generally used in hospitals as a short-acting opioid. With prolonged use, however, fentanyl is stored in fat cells, as it is lipid soluble. This means that an otherwise short-acting opioid can become variable acting, as fat cells may continue to release the opioid for up to several days.

7. Carfentanil is an analogue of fentanyl and is the most potent commercially available opioid, at 10,000 times the potency of morphine and 100 times the potency of fentanyl. It was intended for anesthesia in large animals only; however, it is also being mixed into other illicit drugs, such as heroin, and even a small amount can be extremely toxic.

8. Methadone is a synthetic opioid used primarily as OAT (see Opioid Agonist Therapy, below) for individuals with OUD to manage cravings and withdrawal symptoms. It is characterized by a long half-life with considerable individual variability. Methadone is used less frequently in the treatment of moderate to severe pain. Significant adverse effects include respiratory depression, which can be persistent due to the long half-life, and prolongation of the QTc interval leading to a risk of arrhythmia.

9. Buprenorphine can be used for pain management; however, it is more commonly used for OAT when formulated with naloxone for patients with OUD. It is a partial agonist of mu-opioid receptors with high affinity and low intrinsic agonist activity, which means that it preferentially binds to opioid receptors and displaces lower affinity opioids. If initiated in a patient taking therapeutic or recreational full opioid agonists, it can precipitate severe withdrawal symptoms.

Buprenorphine has a slow onset of action and a plateau, or ceiling effect, meaning that above a certain dose (usually 24 mg) there is less risk of adverse effects such as respiratory depression and intoxication as compared with a full opioid agonist like methadone. It has a long half-life and can relieve pain and withdrawal symptoms for >24 to 36 hours. It has poor gastrointestinal (GI) absorption and is therefore most effective when administered sublingually (tablet or film) or transdermally (patch; brand name BuTrans). It is becoming increasingly available as an implant or subcutaneous injection.

The coformulation buprenorphine/naloxone (brand name Suboxone) was created for the treatment of OUD (see Opioid Agonist Therapy, below), as it reduces the abuse potential of this medication. Naloxone has no effect when taken sublingually but acts as an opioid antagonist if the medication is crushed and injected, which can lead to withdrawal symptoms and reduces the risk of overdose.

TreatmentTop

General Treatment of OUD

It is important to develop a patient-centered approach to OUD treatment. This means taking into account patient values, preferences, and individual stage of change, and working with the patient “where they are at” in terms of readiness to change during your encounter.

1. Psychosocial support: Psychosocial supports should be routinely offered to all patients. These may vary by region. An example of psychosocial support is counseling, which can be either individual or group therapy that is inpatient or outpatient.

It is important to note that willingness to participate in psychosocial supports should not be mandatory in order to engage in other forms of treatment, such as OAT.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity in findings from randomized controlled trials. Bruneau J, Ahamad K, Goyer MÈ, et al; CIHR Canadian Research Initiative in Substance Misuse. Management of opioid use disorders: a national clinical practice guideline. CMAJ. 2018 Mar 5;190(9):E247-E257. doi: 10.1503/cmaj.170958. PMID: 29507156; PMCID: PMC5837873.

2. OAT includes buprenorphine/naloxone, methadone, and SROM. Guidelines recommend initiation of OAT for patients with OUD rather than encouraging an opioid taper or withdrawal management alone.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Degenhardt L, Bucello C, Mathers B, et al. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. Addiction. 2011 Jan;106(1):32-51. doi: 10.1111/j.1360-0443.2010.03140.x. Epub 2010 Nov 4. PMID: 21054613. Sordo L, Barrio G, Bravo MJ, et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017 Apr 26;357:j1550. doi: 10.1136/bmj.j1550. PMID: 28446428; PMCID: PMC5421454. This recommendation is based on studies showing reduced relapse, morbidity, and mortality rates for patients treated with OAT.

OAT should also be considered in patients with acute opioid withdrawal, regardless of whether they meet the definition of OUD.

Choice and dosage of opioid agonists: see Opioid Agonist Therapy, below.

3. Withdrawal management alone and opioid taper: As noted above, patients should be offered OAT in the setting of OUD. Withdrawal management should not be offered alone (without access to long-term treatment). However, if this is the patient’s preference, they should be counseled on the risks and connected with long-term addiction treatment. Also see Acute Opioid Withdrawal in the Emergency Department.

If the patient wishes to discontinue a prescribed opioid (which has led to OUD) through withdrawal management alone, then they should be encouraged to participate in a physician-supervised, slow taper. There are currently no evidence-based tapering protocols.

4. Additional withdrawal-associated symptom management: Withdrawal-associated symptom management alone (without OAT) is not recommended, as noted above. However, if this approach is taken, the following medications can be used for management of withdrawal-associated symptoms. Further, these medications can be used as adjuvants for withdrawal symptoms during initiation or titration of OAT.

1) Headache, myalgia, and other types of pain: Oral acetaminophen up to 1000 mg qid or oral ibuprofen up to 400 mg tid, as needed.

2) Vomiting: Metoclopramide 10 mg used orally, IM, or IV; dimenhydrinate 50 mg orally, IM, or IV; ondansetron 4 to 8 mg orally or IV every 8 hours as needed.

3) Diarrhea: Loperamide: Start with 4 mg orally, then switch to 2 mg orally after each loose stool, up to a total daily dose of 16 mg.

4) Anxiety, restlessness, psychomotor agitation: Oral clonidine 0.1 to 0.3 mg every 1 hour as needed; maximum 1.2 mg/d for initial treatment. Maintenance dosing usually consists of 0.1 mg given orally every 6 hours as needed. Monitor for, and use with caution in patients with, bradycardia and hypotension.

5) Muscle twitching: Oral baclofen 5 to 10 mg tid as needed.

5. Harm reduction: Harm reduction refers to strategies focused on minimizing the negative impacts associated with substance use and are rooted in principles of human rights, social justice, and minimizing stigmatization. As noted above, patients should be met “where they are at” regarding their readiness to change. No matter their stage of change, harm reduction measures should be supported. These may include (but are not limited to):

1) Safe injection practices (eg, do not inject substances alone, start with a test dose).

2) Access to safe injection supplies (eg, sterile supplies).

3) Knowledge regarding supervised injection spaces.

4) Universal provision of a naloxone kit with instructions on how to use it.

6. Referrals/resources: Before discharge patients should be provided with community resources and follow-up. Each jurisdiction is different in terms of their offering. It is useful to familiarize yourself with the resources available in your community. Examples of online and community resources:

1) Online resources:

a) Mentoring, Education, and Clinical Tools for Addiction: Primary Care-Hospital Integration: www.metaphi.ca.

b) Centre for Addiction and Mental Health: www.camh.ca.

2) Ontario community resources:

a) Rapid access addiction medicine clinics: Across Ontario, these can be found at www.metaphi.ca.

b) Counseling resources: Often offered through public health, such as the Alcohol, Drug & Gambling Services of Hamilton (www.hamilton.ca) or Community Addictions Services of Niagara (cason.ca).

c) Harm reduction resources: Consider contacting your local AIDS or public health network, such as Community AIDS Treatment Information Exchange (www.catie.ca).

d) Ontario Disability Support Program application: Consider contacting local clinics.

Opioid Agonist Therapy

In the hospital, OAT is prescribed either to continue the patient’s existing therapy or as a new medication used to treat OUD. The decision to start one OAT over another is multifactorial and must be both evidence based and patient focused, including taking into account patient preference.

When first started on any OAT, patients receive their doses daily and are witnessed at the pharmacy. As they stabilize, they can be provided with take-home doses (also known as “carries”). This process should be led by a physician with comfort and expertise in caring for patients with OUD.

Continuing OAT

If the patient presents to the hospital and is already receiving OAT, before prescribing their OAT be sure to call their pharmacy to confirm their last witnessed dose and the dose amount. Depending on the OAT, failure to make this confirmation can result in severe precipitated withdrawal (buprenorphine/naloxone) or overdose (methadone, SROM) in the case of dose nonadherence.

Starting OAT

This chapter only describes a traditional buprenorphine/naloxone induction protocol. Increasingly, those with expertise in prescribing buprenorphine/naloxone are using microdosing protocols. At this time, such protocols are off-label and require further study, and thus they are not detailed here.

1. First-line therapy: Buprenorphine/naloxone is recommended, whenever feasible, as the first-line treatment for patients with OUD.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and the risk of bias. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014 Feb 6;(2):CD002207. doi: 10.1002/14651858.CD002207.pub4. PMID: 24500948. Bruneau J, Ahamad K, Goyer MÈ, et al; CIHR Canadian Research Initiative in Substance Misuse. Management of opioid use disorders: a national clinical practice guideline. CMAJ. 2018 Mar 5;190(9):E247-E257. doi: 10.1503/cmaj.170958. PMID: 29507156; PMCID: PMC5837873. It should generally not be administered for the first time until the patient develops moderate withdrawal symptoms, as measured by an opioid withdrawal score; this is due to the risk of precipitated withdrawal (see Opioids, above).

In most jurisdictions physicians do not require an exemption to prescribe buprenorphine/naloxone, but it is important to be knowledgeable about this medication. Please consult your local regulatory guidelines (eg, from the College of Physicians and Surgeons of Ontario).

Several useful tools are available for assessing withdrawal severity. The Clinical Opiate Withdrawal Scale (COWS) and the Subjective Opiate Withdrawal Scale (SOWS) are two such scales:

1) COWS (available at mdcalc.com): Assessment is made by a clinician, nurse, or addiction specialist before starting treatment and then every hour until the patient is comfortable.

a) 0 to 12 points (mild withdrawal): Symptomatic treatment.

b) >12 points (moderate to severe withdrawal): Safe to start buprenorphine/naloxone induction.

2) SOWS (available at www.smartcjs.org.uk): Assessment is made by the patient, 1 to 2 times a day, and it is used as a basis for decisions on treatment:

a) 0 to 10 points (mild withdrawal): Symptomatic treatment.

b) 10 to 20 points (moderate withdrawal): Continue symptomatic treatment. It is also safe to start buprenorphine/naloxone induction.

c) 20 to 30 points (severe withdrawal): Safe to start buprenorphine/naloxone induction.

The time of onset of withdrawal symptoms varies depending on the type of opioid taken. General timelines to consider:

1) Short-acting opioids (eg, hydromorphone): 12 to 16 hours.

2) Intermediate-acting opioids (eg, hydromorphone extended-release): Up to 24 hours.

3) Long-acting opioids (eg, methadone, fentanyl): Variable, may be >48 hours (see Opioids, above).

Dosage: Buprenorphine/naloxone is administered sublingually and doses must be witnessed. Formulations come in 2-mg and 8-mg tablets. The 2-mg tablets contain 2 mg of buprenorphine and 0.5 mg of naloxone, while the 8-mg tablets contain 8 mg of buprenorphine and 2 mg of naloxone.

1) Day 1:

a) If the patient is in moderate withdrawal, administer a 2-mg sublingual dose.

b) Reassess the COWS in 1 to 2 hours. If the score increases (withdrawal worsens), consider if the patient is experiencing precipitated withdrawal (see Opioids, above). If this has happened, consider stopping the induction, providing symptomatic relief, and either admitting the patient to the hospital or referring them to an outpatient addiction specialist to try again the next day. If the score remains the same or decreases, administer an additional dose of 2 mg sublingually.

c) Continue to reassess the withdrawal score and administer additional doses until the patient is comfortable. The maximum recommended dose on day 1 is 8 mg sublingually.

2) Day 2: Administer the cumulative dose delivered on day 1 as a single sublingual dose in the morning. Continue to monitor for withdrawal symptoms. You can provide additional doses, at 2- to 4-mg increments, up to a recommended day 2 maximum dose of 16 mg sublingually.

3) Day 3 onward: Administer the previous day’s cumulative dose as a single sublingual dose in the morning. You can provide dose increases at 2- to 4-mg increments up to a maximum daily total of 24 mg sublingually, as needed. The goal is to stabilize the patient on the lowest once-daily dose that provides adequate relief of cravings and withdrawal symptoms.

4) Missed doses: Once on a stable dose, the patient can miss up to 5 days before needing to adjust dosing. This is especially important to remember when ordering home medications for new inpatients. Remember to call the patient’s pharmacy and confirm their dose amount and their last witnessed dose prior to administering their home dose in the hospital. Failure to make this confirmation can result in severe precipitated withdrawal in the case of dose nonadherence.

2. Second-line therapy: Methadone is recommended in patients interested in starting OAT when buprenorphine/naloxone is not the preferred option.Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014 Feb 6;(2):CD002207. doi: 10.1002/14651858.CD002207.pub4. PMID: 24500948.

Methadone is QTc prolonging and should be avoided in patients with prolonged QTc. Monitor the QTc for patients who are receiving other medications that are QTc prolonging. Prescribing methadone likely requires special training or licensing. Please consult your local regulatory guidelines (eg, from the College of Physicians and Surgeons of Ontario).

Dosage (likely to vary by local prescribing guidelines):

1) Days 1 to 3: The initial dose is 15 to 30 mg orally (liquid) once daily. Provide the same dose for 3 days. Lower doses are recommended if the patient has had recent periods of abstinence or lower opioid tolerance, is receiving other sedating medications, has concurrent respiratory illness, or has decompensated liver disease.

2) Day 4 onward: In case of ongoing withdrawal, you can increase the dose by 5 to 15 mg every 3 to 5 days. Dose increases should not be >20 mg within 1 week. An effective maintenance dose takes several weeks to reach and is often between 60 and 120 mg, depending on the patient’s history of opioid use and tolerance.

3) Missed doses: Once on a stable dose, the patient can miss a maximum 2 days before needing to adjust dosing. This is especially important when ordering home medications for new inpatients. Remember to call the patient’s pharmacy and confirm their dose amount and their last witnessed dose prior to administering their home dose in the hospital. Failure to make this confirmation can result in severe overdosing in the case of dose nonadherence.

3. Third-line: SROM is an alternative option for patients in whom buprenorphine/naloxone and methadone are not tolerated or are ineffective.Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and the risk of bias. Klimas J, Gorfinkel L, Giacomuzzi SM, et al. Slow release oral morphine versus methadone for the treatment of opioid use disorder. BMJ Open. 2019 Apr 2;9(4):e025799. doi: 10.1136/bmjopen-2018-025799. PMID: 30944135; PMCID: PMC6500187. Bruneau J, Ahamad K, Goyer MÈ, et al; CIHR Canadian Research Initiative in Substance Misuse. Management of opioid use disorders: a national clinical practice guideline. CMAJ. 2018 Mar 5;190(9):E247-E257. doi: 10.1503/cmaj.170958. PMID: 29507156; PMCID: PMC5837873. Starting doses are variable, depending on the patient’s use pattern. If initiated in the hospital, you can start with short-acting oral morphine and convert to SROM.

Prescribing SROM likely requires special training or licensing. Please consult your local regulatory guidelines.

Long-Term Treatment with OAT

Patients are encouraged to remain on therapy for ≥1 year in order to maintain stability. Tapering off OAT increases the risk of relapse. If the patient wishes to engage in a taper, it is recommended that this be physician-supervised and done slowly (over months to years). There are currently no evidence-based tapering protocols.