OPIOID USE DISORDER

• ACRONYMS AND DEFINITIONS

• ASAM - American Society of Addiction Medicine
• COWS - Clinical opiate withdrawal scale
• CR - Controlled-release
• ER - Extended release
• DSM - Diagnostic and Statistical Manual
• IM - Intramuscular
• IR - Immediate release
• PCSS - Providers Clinical Support System
• SAMHSA - Substance Abuse and Mental Health Services Administration
• SL - Sublingual
• SOWS - Subjective opiate withdrawal scale
• OUD - Opiate use disorder
• UDS - Urine drug screening

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• EPIDEMIOLOGY

• Opioid use disorder
• In 2018, 3.7% of the U.S. population 12 years and older (10.3 million people) misused opiates. Of these people, 9.9 million misused prescription opioids, and 808,000 used heroin. Based on a 2018 survey, approximately 2 million people in the U.S. met the DSM-5 criteria for OUD, and more than 25% of patients receiving opioids for chronic pain have OUD. [2]


• Opioid mortality facts
• In 2019, around 71,000 people died from drug overdoses in the U.S., and of these deaths, more than 70% involved a prescription or illicit opioid
• Every day in the United States, more than 130 people die from opioid-related drug overdoses, and approximately one-third of these overdoses involve prescription opioids
• One-third of all opioid deaths involve heroin
• Overdose deaths from opioids have occurred in 3 waves
• First wave (1990s) - increase in deaths that coincided with increased prescribing of opioids by healthcare providers
• Second wave (2010) - rapid increase in the use of heroin
• Third wave (2013 - now) - rise in deaths from synthetic opioids (e.g. fentanyl), which are now involved in 73% of opioid overdose deaths [1,13]

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• PATHOLOGY

• Five types of opioid receptors have been identified in humans - mu receptor (μ), kappa receptor (κ), delta receptor (δ), nociception receptor, and zeta receptor (ζ). Receptors are further divided into subtypes (e.g. mu1, mu2, mu3).
• Opioid mu receptors are the primary target of exogenous opioids (e.g. heroin, morphine, fentanyl); they are also stimulated by endogenous opiates (e.g. enkephalins, endorphins). Mu receptors are located in the brain, spinal cord, gastrointestinal tract, peripheral nerves, and skin. Upon stimulation, they modulate intracellular processes involved in nerve conduction and neurotransmitter release, specifically decreased norepinephrine and increased dopamine. These effects lead to analgesia, euphoria, dependence, respiratory depression, miosis, and decreased GI motility. During chronic opioid use, opiate cessation causes a rebound in norepinephrine activity that is responsible for many of the symptoms seen in opioid withdrawal (e.g. lacrimation, diaphoresis, tachycardia, and mydriasis). [2,3,4]

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• OPIATE HALF-LIVES

• ^✝The half-life of methadone is highly variable, with a duration of anywhere from 8 to 59 hours
• Opiate products that come in extended- and controlled-release versions may have longer durations of action that affect when withdrawal may occur
• References [2,7]

OPIATE HALF-LIVES During chronic use, withdrawal symptoms may begin after 1 - 2 half-lives
Drug	Half-life (hours)
Buprenorphine	24 - 42
Codeine	3
Fentanyl	8 - 10
Heroin	3 - 5
Hydrocodone	4.5
Hydromorphone (Dilaudid®)	2.3
Hydromorphone ER (Exalgo ER®)	11
Meperidine (Demerol®)	3 - 8
Methadone	22 - 24✝
Morphine	2 - 4
Morphine CR (Kadian®)	11 - 13
Oxycodone IR	3.5 - 4
Oxycodone ER (Oxycontin®)	4 - 5
Oxymorphone	7 - 10
Tramadol	6 - 8

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• DIAGNOSIS

• DSM-5 opiate use disorder diagnostic criteria
• The DSM-5 OUD criteria are presented below. The criteria consist of 11 true or false items that pertain to opiate use, and OUD is categorized as mild, moderate, or severe based on the number of symptoms present.
• Mild: 2 to 3 symptoms present
• Moderate: 4 to 5 symptoms present
• Severe: ≥ 6 symptoms present
• The table below lists the criteria as they are described in the DSM-5. A link to a pdf form that presents the items as questions to the patient is also provided.


• DSM-5 OUD criteria patient questionnaire (pdf)

• ^✝ If the opioid is taken only as prescribed, this item does not count toward a diagnosis of OUD
• Reference [2]

DSM-5 Opiate Use Disorder Criteria
Opiate use disorder is diagnosed based on the presence (within the past 12 months) of the 11 symptoms detailed below. The severity of OUD is defined as follows: Mild: 2 to 3 symptoms present Moderate: 4 to 5 symptoms present Severe: ≥ 6 symptoms present
Opioids are often taken in larger amounts or over a longer period of time than intended
There is a persistent desire or unsuccessful efforts to cut down or control opioid use
A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects
Craving or a strong desire to use opioids
Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home
Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids
Important social, occupational, or recreational activities are given up or reduced because of opioid use
Recurrent opioid use in situations in which it is physically hazardous
Continued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids
✝Tolerance, as defined by either of the following: A need for markedly increased amounts of opioids to achieve intoxication or desired effect Markedly diminished effect with continued use of the same amount of an opioid
✝Withdrawal, as manifested by either of the following: The characteristic opioid withdrawal syndrome The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms

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• WITHDRAWAL SYMPTOMS

• Symptoms
• The opiate withdrawal syndrome is marked by a loss of opiate receptor stimulation that leads to a rebound in norepinephrine activity. The onset of withdrawal is dependent upon the half-life of the opiate being used. For short-acting opiates like heroin (half-life of 3 - 5 hours), withdrawal symptoms typically appear within 12 hours of last use. For long-acting opiates like methadone (half-life up to 96 hours), withdrawal symptoms may not occur for 1 - 3 days. The duration of withdrawal is also related to the half-life; symptoms of heroin withdrawal typically last 4 - 5 days, while methadone withdrawal can last 1 - 2 weeks. Opiate antagonists (e.g. naloxone, naltrexone) can precipitate withdrawal within minutes, depending on how they are administered. See opiate half-lives for more information.
• Symptoms of opiate withdrawal may include any of the following:
• Muscle aches
• Increased tearing
• Runny nose
• Sweating
• Nausea / vomiting
• Diarrhea
• Abdominal cramping
• Dilated pupils (mydriasis)
• Piloerection (goosebumps)
• Agitation / anxiety
• Yawning
• Insomnia [2,3]

• Withdrawal assessment tools
• Two tools that are used to assess the severity of opiate withdrawal are discussed below. The COWS tool is designed to be administered by a healthcare provider, and the SOWS tool is completed by the patient.

• Clinical Opiate Withdrawal Scale (COWS)
• COWS is intended to be administered by a healthcare provider. COWS has 11 components and a score that ranges from 0 to 48. Categories of withdrawal based on COWS are as follows:
• COWS 5 - 12: Mild withdrawal
• COWS 13 - 24: Moderate withdrawal
• COWS 25 - 36: Moderately severe withdrawal
• COWS ≥ 36: Severe withdrawal


• Online COWS calculator
• COWS assessment form (pdf)

• Subjective Opiate Withdrawal Scale (SOWS)
• SOWS is self-administered, which makes it more amenable to outpatient treatment. SOWS assesses 16 symptoms, with each symptom scored from 0 (none) to 4 (extreme). Categories of withdrawal based on SOWS totals are as follows:
• SOWS 1 - 10: Mild withdrawal
• SOWS 11 - 20: Moderate withdrawal
• SOWS ≥ 21: Severe withdrawal


• SOWS assessment form (pdf)

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• TREATMENT

• Whom to treat
• Patients who meet the criteria for OUD (see DSM-5 criteria) are eligible for treatment. Treatment may start during acute opiate withdrawal, or it may be initiated in stable patients to prevent cravings and future unhealthy use. Three drugs are primarily used to treat OUD - buprenorphine, methadone, and naltrexone. Buprenorphine and methadone are long-acting opioids that provide a constant level of opioid activity and have been shown to promote treatment retention, decrease illicit drug use, and improve OUD mortality. They are also preferred when treating acute withdrawal. Naltrexone is an opioid antagonist that blocks the effects of opioids. It can precipitate or worsen acute withdrawal and should only be initiated in patients who have been opiate-free for 7 or more days, depending on the opiate's half-life. [2]

• Acute withdrawal
• The avoidance of opiate withdrawal symptoms is a major factor in continued use. Buprenorphine and methadone alleviate withdrawal symptoms by replacing the discontinued opioid. Other medications can be used to target the symptoms of withdrawal (e.g. antiemetics for nausea).
• For patients who do not desire opioid maintenance therapy, withdrawal may be treated with a short course of buprenorphine or methadone that is quickly tapered; this kind of treatment typically lasts 4 - 6 weeks. Likewise, patients may only receive symptomatic treatment.
• Recommendations for initiating buprenorphine and methadone during acute withdrawal are provided below, along with guidance on drugs used for symptomatic treatment. [2]

• References [2,7]

Buprenorphine

Pharmacology Buprenorphine is a partial opioid mu receptor agonist, which means it stimulates opioid receptors to a degree, but unlike full agonists, it has a ceiling effect. Buprenorphine binds opioid receptors tightly and disassociates slowly; this can cause it to displace full agonists (e.g. heroin, morphine) from the receptors and precipitate withdrawal. When absorbed intestinally, buprenorphine is rapidly metabolized in the liver via the first-pass effect. Because of this, it is only available in sublingual and buccal forms. Pharmacokinetics Onset of action: peak effect in 100 minutes Half-life: 24 - 42 hours Prescribing requirements Providers must obtain a waiver and, in some cases, undergo special training in order to prescribe buprenorphine for OUD. See SAMHSA website for details Prescribing documents Several documents that may be helpful for buprenorphine prescribing are provided below Buprenorphine treatment agreement - document for patients to sign that outlines treatment expectations and buprenorphine precautions Buprenorphine induction - document that explains buprenorphine induction to patients The PCSS also publishes buprenorphine prescribing documents. See PCSS clinical tools for more. Dosage forms There are 3 buprenorphine products used for acute opiate withdrawal - Subutex, Suboxone, and Zubsolv. Subutex contains buprenorphine, while Suboxone and Zubsolv contain buprenorphine and naloxone. Naloxone is included to deter injection of the product. Subutex (buprenorphine) - 2 and 8 mg SL tablet | generic available Suboxone (buprenorphine / naloxone) SL tablet: 2/0.5 mg and 8/2 mg | generic available SL / buccal film: 2/0.5 mg, 4/1 mg, 8/2 mg, 12/3 mg | generic available Zubsolv (buprenorphine / naloxone) - 0.7/0.18 mg, 1.4/0.36 mg, 5.7/1.4 mg, 8.6/2.1 mg, 11.4/2.9 mg SL tablet | no generic Choosing a product For patients who are withdrawing from short-acting opioids, a buprenorphine/naloxone product is recommended for both withdrawal and maintenance treatment. Naloxone is included to deter injection because it will precipitate withdrawal when given parenterally. If the product is taken as instructed, naloxone-induced withdrawal is uncommon. However, if a patient is withdrawing from a long-acting opiate like methadone, naloxone-induced withdrawal may occur with sublingual/buccal administration. Because of this, buprenorphine-only products (Subutex) may be considered initially in these patients. After the patient is stable, therapy should be switched to a buprenorphine/naloxone product. Naloxone (nasal spray or injection) It is strongly recommended that all patients being treated for OUD be prescribed naloxone nasal spray or injection for emergency use (see naloxone below) Switching between products When switching between Subutex, Suboxone SL tablet, and Suboxone SL/buccal film, the buprenorphine dose remains the same; however, some patients may require dose adjustments after switching. Conversions for Zubsolv to other products are provided here - Zubsolv conversions. Dosing NOTE: all dosing is presented as buprenorphine with either Subutex or Suboxone Timing of initial dose Buprenorphine, a partial mu opioid receptor agonist, has the potential to displace full opioid agonists from opiate receptors and precipitate withdrawal. Because of this, it should not be administered too soon after the last opioid use. In general, buprenorphine should be started 6 - 12 hours after the last use of heroin or other short-acting opioids and 24 - 72 hours after using a long-acting opioid like methadone (see opiate half-lives). Patients transitioning from methadone to buprenorphine should have their methadone dose tapered to 30 mg or less for at least 1 week before starting buprenorphine. Opiate withdrawal assessment tools (see COWS and SOWS) can also be used to help time initiation. A COWS or SOWS score of ≥ 11 indicates that it is appropriate to start buprenorphine. First day An initial dose of 2 - 4 mg should be given. If the initial dose is well-tolerated, additional doses of 2 - 4 mg can be given at 2 hour intervals up to a total daily dose of 8 mg. Second day A single daily dose of up to 16 mg is recommended Third day and on The dose can be adjusted in 2 - 4 mg increments up to a total daily dose of 24 mg, with a recommended target dose of 8 - 16 mg once daily. Doses above 24 mg/day have not been shown to provide any further benefit. Length of therapy There is no recommended length of therapy for buprenorphine. Patients should be treated for as long as needed to maintain a stable, healthy life. Some patients may discontinue therapy after their withdrawal is over, while others may remain on buprenorphine for years. In general, treatment for less than 90 days has been found to be less effective than more prolonged therapy. Discontinuing therapy When a decision is made to discontinue therapy, buprenorphine should be gradually tapered to prevent withdrawal. See opioid tapering for recommendations on discontinuing therapy.

• References [2,7]

Methadone

Pharmacology Methadone is a full opioid agonist. Compared to short-acting opioids, it has a slow onset of action and long duration of effect, which helps to reduce the highs (euphoria) and lows (withdrawal) of opiate abuse. Pharmacokinetics Onset of action: peak plasma concentrations in 1 to 7.5 hours Half-life: 22 - 24 hours on average; up to 59 hours in some people Dosage forms Tablet: 5 and 10 mg Dispersible tablet for suspension (Methadose): 40 mg Solution: 5 mg/5 ml, 10 mg/5 ml Concentrate: 10 mg/1 ml See methadone Prescribing requirements Methadone for OUD is available through clinics that have been accredited and certified by SAMHSA as opioid treatment programs. See SAMHSA website for details. Naloxone It is strongly recommended that all patients being treated for OUD be prescribed naloxone nasal spray or injection for emergency use (see naloxone below) Dosing Timing of initial dose Methadone should be started when the patient is experiencing withdrawal symptoms and has no signs of intoxication or sedation First day The recommended initial dose is 10 - 30 mg. For individuals with no or low opioid tolerance (e.g. patients transitioning from naltrexone, patients re-entering the community after residential treatment or incarceration [with no agonist treatment], patients re-initiating methadone after relapse, no opiate use in the past 5 days), use a lower initial dose of 2.5 to 10 mg. Reassess patient in 2 - 4 hours and provide an additional 5 - 10 mg if the patient is still experiencing withdrawal. Do not exceed a total daily dose of 40 mg. Second day and on It's important to consider methadone's long half-life when titrating therapy. Daily dosage increases can cause drug accumulation several days later that raise the risk of oversedation. In general, methadone should be increased by no more than 10 mg every 5 days or 5 mg every 2 - 3 days. Effective maintenance doses are usually in the range of 60 - 120 mg/day. Length of therapy There is no recommended length of therapy for methadone. Patients should be treated for as long as needed to maintain a stable, healthy life. Some patients may discontinue therapy after their withdrawal is over, while others may remain on methadone for years. In general, treatment for less than 90 days has been found to be less effective than more prolonged therapy. For most patients, a minimum of 12 months of therapy is recommended. Discontinuing therapy When a decision is made to discontinue therapy, methadone should be gradually tapered to prevent withdrawal. See opioid tapering for recommendations on discontinuing therapy.

• Reference [5,6]

Symptomatic Treatment of Opiate Withdrawal
Autonomic overactivity (elevated pulse and blood pressure, anxiety, chills, piloerection) Clonidine Clonidine is an alpha-2-agonist that is primarily used to treat hypertension. It works by suppressing sympathetic outflow from the CNS and is therefore useful in treating symptoms of opiate withdrawal. Inpatient setting: starting dose is 0.1 - 0.2 mg every 4 - 8 hours with a maximum dose of 1 mg/day. Hold dose for SBP < 90 mmHg or DBP < 60 mmHg. On day 5, start to decrease dose by 0.2 mg/day. The average duration of treatment is 15 days. Outpatient setting: doses of 0.1 - 0.2 mg two to four times a day are typically used. Blood pressure monitoring is recommended. Lofexidine (Lucemyra®) Lofexidine is an alpha-2 agonist that was FDA-approved to treat opiate withdrawal in 2018. Unlike clonidine, it does not have a generic and is very expensive. Dosing: Three 0.18 mg tablets four times daily during the period of peak withdrawal symptoms. There should be 5 to 6 hours between each dose. Reduce dose over 2 - 4 days (e.g. reduce 1 tablet per dose every 1 - 2 days) See Lucemyra PI for full prescribing information Alternative therapies Baclofen 5 mg three times daily. May increase to 40 mg/day. Re-evaluate in 3 to 7 days. The average duration of treatment is 15 days. May continue after acute withdrawal to help decrease cravings. Taper drug when discontinuing. Gabapentin - start with 100 - 300 mg and titrate to 1800 - 2100 mg/day divided into 2 to 3 doses. It can help reduce withdrawal symptoms and help with pain, anxiety, and sleep. Tizanidine 4 mg three times daily. May increase to 8 mg three times daily.
Insomnia Temazepam 15 - 30 mg at bedtime as needed Trazodone 25 - 300 mg at bedtime as needed
Anxiety Diazepam 2 - 10 mg every 4 hours as needed | Maximum of 20 mg/day Hydroxyzine 25 - 50 mg three times daily as needed
Lacrimation, rhinorrhea Hydroxyzine 25 - 50 mg three times daily as needed Diphenhydramine 25 mg every 6 hours as needed
Diarrhea Loperamide (Imodium®) 4 mg initially followed by 2 mg as needed for loose stools; maximum of 16 mg/day
Joint pain, body aches Naprosyn 500 mg twice daily as needed Ibuprofen 800 mg three times a day as needed Acetaminophen 650 mg every 6 hours as needed
Nausea and vomiting Ondansetron (Zofran®) 8 mg every 8 hours as needed Prochlorperazine (Compazine®) 5 - 10 mg by mouth every 4 hours as needed | Daily doses > 40 mg should only be used in severe cases Promethazine 25 mg oral/rectal every 6 hours as needed
Abdominal cramping Dicyclomine 20 mg every 6 - 8 hours as needed

• Maintenance therapy
• Patients with OUD who receive maintenance therapy have a lower risk of relapse, higher treatment retention, less illicit drug use, and improved mortality. Maintenance therapy should include both psychosocial and pharmacological modalities. If buprenorphine or methadone are used to treat acute withdrawal, they can be continued in the maintenance phase. If therapy is started after withdrawal has passed, naltrexone may also be considered.

• Psychosocial
• Psychosocial treatment may consist of one-on-one therapy with a mental health/addiction specialist and/or support groups. Links to some popular OUD support networks are provided below.
• Narcotics anonymous
• Medication-assisted recovery anonymous
• Self-Management and Recovery Therapy (SMART)

• Buprenorphine and Methadone
• Maintenance therapy with buprenorphine or methadone can continue for as long as needed. See buprenorphine and methadone for recommendations on dosing. [2]

• Naltrexone
• Naltrexone is an opioid antagonist that binds to opioid receptors and blocks the effects of opiates. It is available as a once-daily pill and an intramuscular injection that is given every 4 weeks. Most guidelines do not recommend oral naltrexone unless pill administration is supervised. Naltrexone should only be initiated in patients who are past the withdrawal phase of opiate abuse because it can worsen withdrawal symptoms. In general, at least 6 opioid-free days should pass before initiating naltrexone in patients who are stopping short-acting opioids, and 7 - 10 days should pass for long-acting opioids like methadone and buprenorphine. To see if patients have completed withdrawal, a naloxone challenge may be performed.
• There is no recommended length of therapy for naltrexone. Patients should be treated for as long as needed to maintain a stable, healthy life.
• See naltrexone for full prescribing details [2]

• Pain management patients
• Patients prescribed opiates for chronic pain may want to stop them for different reasons (e.g. lack of efficacy, side effects). They may also develop OUD that necessitates intervention.
• Patients who wish to discontinue their prescription opiate can be tapered off the drug as other pain therapies are initiated (see opioid tapering). Patients who develop OUD and are abusing prescription opiates may need to be transitioned to buprenorphine or methadone. Initiating therapy in these patients follows the same principles as in other types of OUD (see acute withdrawal).

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• ACUTE PAIN / SURGERY

• Treating acute pain
• Patients on OUD therapy with acute pain should be treated with non-opioid analgesics (e.g. NSAIDs, acetaminophen) in most cases. When stronger pain control is needed, the recommendations below can be helpful while keeping in mind that there is no one-size-fits-all approach to treating pain in these patients, and every plan must be tailored to the individual.

• Methadone-treated patients (one or more of the following)
• Temporarily increase the dose of methadone
• Divide the daily methadone dose into 3 - 4 doses and give it over the course of a day. This is based on the fact that the analgesic effect of methadone usually lasts 6 - 8 hours, while withdrawal suppression lasts 24 - 36 hours.
• Add a short-acting full opioid agonist. The dose of the full agonist will likely need to be higher than what is usually required. This strategy should be done with extreme caution since it increases the risk of oversedation. [2]

• Buprenorphine-treated patients (one or more of the following)
• Temporarily increase the daily dose of buprenorphine by 20 - 25%
• Divide the daily buprenorphine dose into 3 - 4 doses and give it over the course of a day. This is based on the fact that the analgesic effect of buprenorphine usually lasts 6 - 8 hours, while withdrawal suppression lasts 24 hours.
• Use a combination of the temporary increase and dose dividing
• Provide additional as-needed doses of buprenorphine
• Add a short-acting full opioid agonist. The dose of the full agonist will likely need to be higher than what is usually required. This strategy is only recommended in an inpatient setting. [2]

• Naltrexone-treated patients
• Non-opioid analgesics, including high-potency NSAIDs (e.g. ketorolac), should be used when appropriate
• In emergency situations, the following may be necessary:
• Regional anesthesia
• Conscious sedation with benzodiazepines or ketamine
• Nonopioid options in general anesthesia
• Overriding the naltrexone blockade with high-potency opioids (only in monitored settings) [2]

• Patients requiring surgery
• Buprenorphine and methadone
• Methadone and buprenorphine do not need to be discontinued before surgery. High-potency intravenous full opioid agonists can be used perioperatively for analgesia.
• If buprenorphine and methadone are discontinued before planned surgery, they should be stopped the day before or the day of surgery. They may be resumed when intravenous analgesia is no longer required. If they are withheld for 2 - 3 days, they can be restarted at the prior maintenance dose. If they are withheld for more than 3 days, re-titration may be necessary.
• Naltrexone
• Oral naltrexone should be discontinued at least 72 hours before planned surgery
• Intramuscular naltrexone should be stopped at least 30 days before surgery. After 30 days, oral naltrexone may be used up to 72 hours before surgery.
• After surgery, patients should be off opiates for 3 - 7 days before restarting naltrexone
• If the procedure does not require opioid use, it may be reasonable to continue naltrexone uninterrupted [2]

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• LABORATORIES

• Initial labs
• All patients should have a CBC and CMP when starting therapy. Patients who inject drugs should be screened for hepatitis B, hepatitis C, and HIV. Patients with high-risk sexual behavior should be screened for all of the above, plus gonorrhea, chlamydia, and syphilis. TB testing should be considered in patients who are homeless, live in group homes, or have a history of incarceration.

• Urine drug screening (UDS)
• Urine drug testing is used to monitor therapy compliance and screen for illicit drug use. Other testing methods are available (e.g. hair, blood, saliva, sweat), but urine is the most widely used and preferred modality because it is cost-effective and convenient.

• Methodology
• Most UDS samples are initially screened with an immunoassay, where antibodies to specific drugs (or their metabolites) are mixed with the urine. If a drug is not present, its antibodies will bind to a conjugate compound, and a line will form in the readout area. If the drug is present in sufficient quantity, the antibody will bind the drug, and a line will not appear. Tests vary in the amount of drug that must be present (the cutoff value) in order to register a positive result. Because of this, two different tests may give discordant results. Positive immunoassay results are often referred to as "presumptive positive" since further testing is required to achieve a definitive result.
• Immunoassay results can be confirmed with gas or liquid chromatography followed by mass spectrometry. Chromatography is a lab technique used to separate compounds in a specimen, and mass spectrometry identifies the compound based on its molecular weight. Chromatography/spectrometry is more sensitive and specific than immunoassay, but it is also more expensive. Whether or not positive immunoassay results should be confirmed with chromatography/spectrometry depends on the situation. If a patient admits to the positive immunoassay result or its findings have no bearing on overall care, further testing isn't indicated. If test results are part of a legal matter, they should definitely be confirmed. [8]

• Frequency
• There is no flat, one-size-fits-all consensus recommendation on UDS frequency because individual factors (e.g. stability, treatment type, treatment setting) largely determine its utility. In general, weekly testing is appropriate at the beginning of therapy, with a switch to monthly or less frequent testing once the patient is stable. If plausible, random testing is favored over a set schedule. Federal law mandates that patients who are being treated in a SAMHSA-certified opioid treatment program be tested a minimum of 8 times a year. [8]

• Validity testing
• Some patients may attempt to alter their urine samples in order to prevent a positive result. A common tampering method is to dilute the urine specimen by overhydrating, taking diuretics, or adding fluids to it. Masking agents that destroy the presence of the drug or interfere with the immunoassay are also used. Proper specimen collection procedures can help to prevent some of these actions, but nothing is foolproof, and the validity of a specimen may need to be confirmed. The urine tests discussed below can be used to test the legitimacy of a sample. Whether these tests are performed depends on the circumstances surrounding the testing.


• Urine creatinine - urine creatinine concentrations can be used to detect adulterated samples. A concentration of < 20 mg/dl is a sign of dilution and renders the sample invalid. Very high concentrations can be a sign of adulterants.
• Urine specific gravity - a normal urine specific gravity is 1.005 - 1.035. A specific gravity of ≤ 1.000 is consistent with dilution, while a reading > 1.035 can occur with adulterants.
• Urine pH - a normal urinary pH is 5 - 9. Abnormal urinary pH can affect the stability of drugs and their metabolites, as well as the performance of immunoassays. Contamination with bleach, vinegar, acid, soap, or detergent can alter the pH of a sample. Patients on low-carbohydrate diets may also have a low pH.
• Immunoglobulin G (IgG) - IgG is normally present in human urine. Levels less than 0.5 mcg/ml are consistent with synthetic or animal urine. Urinary IgG assays are not widely available.
• Adulterant testing - testing that identifies specific adulterants is available but is not widely used [8]

• Drug panel interpretation
• Drug panels vary by which substances they detect. Almost all assays include cannabinoids, phencyclidine (PCP), opiates, amphetamines, and cocaine. More extensive panels can detect specific opiates, ethanol, and other substances of abuse. In general, drugs are detectable in the urine for 1 - 3 days after single-use, while chronic daily users may have detectable levels for longer periods. One notable exception is ethanol, which has a detection window of only 10 - 12 hours. Drug panel interpretation is discussed in the table below.

• In general, drugs are detectable in the urine for 1 - 3 days after single-use, while chronic daily users may have detectable levels for longer periods
• Reference [8,9,14]

UDS interpretation
Amphetamines Detectable in urine for 48 hours Standard immunoassays detect amphetamine, a metabolite of methamphetamine Some ADHD drugs contain amphetamine (e.g. Adderall) Part of standard workplace screen
Barbiturates Short-acting barbiturates (e.g. pentobarbital) is detectable in urine for 24 hours Long-acting barbiturates (e.g. phenobarbital) is detectable in urine for up to 3 weeks
Benzodiazepines Short-acting benzos (e.g. lorazepam) are detectable in urine for 3 days Long-acting benzos (e.g. diazepam) are detectable in urine for up to 30 days Immunoassays may not detect benzodiazepines when they are used at therapeutic doses Some tests have low sensitivity for clonazepam and lorazepam More sensitive testing (e.g. chromatography) may be required to confirm negative results Certain benzodiazepines are metabolized to other benzodiazepines, so confirmation testing may show multiple benzos when only one was consumed. For example, chlordiazepoxide and diazepam are both metabolized to temazepam and oxazepam.
Buprenorphine Detectable in urine for 4 - 10 days Buprenorphine is metabolized to norbuprenorphine, which is usually present in greater concentrations. Urinary immunoassays only detect buprenorphine and not norbuprenorphine. Patients can place a small amount of buprenorphine in their sample, and it will make it positive for buprenorphine. Confirmatory testing (chromatography/spectrometry) will detect buprenorphine and norbuprenorphine. A sample that contains a ratio of norbuprenorphine to buprenorphine of < 0.02 suggests that it was tampered with by adding buprenorphine directly to the urine. Does not cause a positive opiate test. Must be detected separately
Cannabinoids Single use is detectable in the urine for 3 days. Chronic use may be detectable for up to 30 days. Detects the THC metabolite THC-9-carboxylic acid (THC-COOH) Part of standard workplace screen
Cocaine Detectable in urine for 2 - 4 days Detects the cocaine metabolite benzoylecgonine (BZE) Test is very sensitive and specific Part of standard workplace screen
Ethanol Only detectable for 10 - 12 hours after consumption Ethanol metabolites ethyl glucuronide and ethyl sulfate are detectable for up to 5 days but must be ordered separately
Fentanyl Detectable in urine for 1 - 2 days Does not cause a positive opiate test. Must be detected separately
Heroin Detectable in urine for 1 - 3 days Identified by its metabolite 6-Monoacetylmorphine (6-MAM) Causes a positive opiate result
Methadone Detectable for 3 - 11 days with maintenance dosing Does not cause a positive opiate test. Must be detected separately.
MDMA Detectable in urine for 1 - 3 days Methylenedioxymethamphetamine (Ecstasy) False positives from trazodone and bupropion have been reported
Opiates Detectable in urine for 2 - 4 days Morphine, codeine, heroin, hydrocodone, and hydromorphone cause a positive result Meperidine, methadone, buprenorphine, and fentanyl do not cause a positive result Oxycodone and oxymorphone cause a positive result 1 - 10% of the time Poppy seeds contain codeine and morphine and may cause a false-positive result. Most immunoassays use cutoff values that prevent positive results from poppy seed consumption. On confirmation testing, codeine and morphine values > 2000 ng/ml are consistent with opioid use as opposed to poppy seed consumption. Part of standard workplace screen
Oxycodone Detectable in urine for 2 - 4 days Causes a positive opiate test 1 - 10% of the time Detected with a separate test
Phencyclidine (PCP) Detectable in urine for up to 8 days Part of standard workplace screen

• False-positive results
• The first step in urine drug testing is to screen the sample with an immunoassay, which uses antibodies to detect drugs (see methodology). These antibodies can crossreact with compounds that have a similar structure to the test drug, causing a false positive. A number of case reports have implicated a long list of substances as causing false-positive results. It's difficult to know which entities actually cause consistent false positives because immunoassays vary, and in general, individual tests have not been evaluated in this manner. Two papers that provide lists of drugs and other substances that have been reported to cause false-positive results are provided below.
• Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens, Mayo Clin Proc (2017) [PubMed abstract]
• False-positive interferences of common urine drug screen immunoassays: a review, J Anal Toxicol (2014) [PubMed abstract]

• Urinary opiate metabolites
• The table below may be helpful when interpreting results from chromatography/spectrometry testing for opiates

---

• BUPRENORPHINE (CIII)

• Subutex® (buprenorphine)
• Sublingual tablet
• 2 mg
• 8 mg
• Generic available: $-$$ for #60


• Dosing
• See acute withdrawal for recommendations on initiating buprenorphine during opiate withdrawal
• Day 1: 4 - 8 mg given 12 - 48 hours after most recent opioid use while patient is having withdrawal symptoms
• Day 2: dose may be increased up to 16 mg
• Days 3 - 7: dose may be increased up to 24 mg
• Maintenance: 4 - 24 mg once daily with a target dose of 8 - 16 mg once daily
• Do not cut, chew, or swallow tablets. Do not eat or drink anything until the tablet is completely dissolved.
• For doses requiring more than two tablets, patients are advised to place all the tablets at once or place two tablets at a time
• After tablets have dissolved, patient should swish and swallow with water. Wait at least 1 hour before brushing teeth
• It is strongly recommended that all patients being treated for OUD be prescribed naloxone for emergency use (see naloxone below)
• Switching between products:
• When switching between Subutex, Suboxone SL tablet, and Suboxone SL/buccal film, the buprenorphine dose remains the same; however, some patients may require dose adjustments after switching. Conversions for Zubsolv to other products are provided here - Zubsolv conversions. [7]

• Suboxone® (buprenorphine + naloxone)
• Sublingual tablet
• Buprenorphine (mg) : Naloxone (mg)
• 2 mg : 0.5 mg
• 8 mg : 2.0 mg
• Generic available: $$-$$$ for sixty 8/2 mg tablets


• Sublingual/buccal film
• Buprenorphine : Naloxone
• 2 mg : 0.5 mg
• 4 mg : 1.0 mg
• 8 mg : 2 mg
• 12 mg: 3 mg
• Generic available: $$$ for sixty 8/2 mg films


• Dosing
• NOTE: all dosing expressed in terms of buprenorphine component
• See acute withdrawal for recommendations on initiating buprenorphine during opiate withdrawal
• Day 1: 4 - 8 mg given 12 - 48 hours after most recent opioid use while patient is having withdrawal symptoms
• Day 2: dose may be increased up to 16 mg
• Days 3 - 7: dose may be increased up to 24 mg
• Maintenance: 4 - 24 mg once daily with a target dose of 8 - 16 mg once daily
• It is strongly recommended that all patients being treated for OUD be prescribed naloxone for emergency use (see naloxone below)
• Tablets
• Do not cut, chew, or swallow tablets. Do not eat or drink anything until the tablet is completely dissolved.
• For doses requiring more than two tablets, patients are advised to place all the tablets at once or place two tablets at a time
• After tablets have dissolved, patient should swish and swallow with water. Wait at least 1 hour before brushing teeth
• Films
• Films may be administered sublingually or buccally. Do not cut, chew, or swallow films. Do not move films after placement.
• Exposure to naloxone is somewhat higher with buccal administration; therefore, it is recommended that films be given sublingually during induction to minimize exposure to naloxone. After induction, patients may switch between sublingual and buccal administration.
• Sublingual: Place one film under the tongue, close to the base on the left or right side. If an additional film is necessary, place it on the opposite side from the first film. Try to limit film overlapping. Leave film(s) in place until it dissolves. If a third film is necessary, place it under the tongue on either side after the first 2 films have dissolved.
• Buccal: Place one film on the inside of the right or left cheek. If an additional film is necessary, place it on the inside of the opposite cheek. Leave film(s) in place until it dissolves. If a third film is necessary, place it on the inside of the right or left cheek after the first two films have dissolved.
• Switching between products
• When switching between Subutex, Suboxone SL tablet, and Suboxone SL/buccal film, the buprenorphine dose remains the same; however, some patients may require dose adjustments after switching. Conversions for Zubsolv to other products are provided here - Zubsolv conversions.
• When switching between different strengths of Suboxone films (e.g. three 4 mg films to one 12 mg film), systemic exposures of buprenorphine and naloxone may be different, and patients should be monitored for changes in efficacy and side effects. [7]

• Zubsolv® (buprenorphine + naloxone)
• Sublingual tablet
• Buprenorphine : Naloxone
• 0.7 mg : 0.18 mg
• 1.4 mg : 0.36 mg
• 5.7 mg : 1.4 mg
• 8.6 mg : 2.1 mg
• 11.4 mg : 2.9 mg
• No generic: $$$$ for thirty tablets


• Dosing
• See acute withdrawal for recommendations on initiating buprenorphine during opiate withdrawal
• Day 1: start with 1.4/0.36 mg and repeat every 1.5 - 2 hours as needed up to a total daily dose of 5.7/1.4 mg
• Day 2: single daily dose of up to 11.4/2.9 mg is recommended
• Days 3 and on: increase dose in increments of 2.9/0.71 mg up to a total daily dose of 17.2/4.2 mg
• Maintenance: 2.9/0.71 mg to 17.2/4.2 mg once daily with a target dose of 5.7/1.4 - 11.4/2.9 mg once daily
• Do not cut, chew, or swallow tablets. For dosages requiring more than one tablet, place all tablets in different places under the tongue simultaneously, or place tablets sequentially while letting each one dissolve completely before administering the next.
• It is strongly recommended that all patients being treated for OUD be prescribed naloxone for emergency use (see naloxone below) [7]

• Reference: Zubsolv PI

Suboxone / Zubsolv Conversion
Suboxone dose	Zubsolv dose
2/0.5 mg	1.4/0.36 mg
4/1 mg	2.9/0.71 mg
8/2 mg	5.7/1.4 mg
12/3 mg	8.6/2.1 mg
16/4 mg	11.4/2.9 mg

• Probuphine® (buprenorphine)
• Subdermal implant
• Each implant contains 80 mg of buprenorphine HCL
• Comes in kit with 4 implants and disposable applicator
• No generic. $$$$ for 4 implants


• Dosing
• Approved for the maintenance treatment of opioid dependence
• Dosing: Four implants inserted subdermally in the inner side of the upper arm every 6 months
• Patients should be on stable (≥ 3 months) maintenance doses of ≤ 8 mg/day of Subutex or Suboxone. For Bunavail, stable maintenance doses should be ≤ 4.2 mg/0.7 mg. For Zubsolv, stable maintenance doses should be ≤ 5.7 mg/1.4 mg.
• If another insertion is desired after 6 months, the opposite arm should be used
• After one insertion in each arm, patients should be transitioned back to transmucosal buprenorphine. Reinserting Probuphine in a previously-treated arm has not been studied. [7]

• Sublocade® (buprenorphine)
• Prefilled syringe
• 100 mg
• 300 mg
• No generic. $$$$ for 1 syringe


• Dosing
• Indicated for patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. Patients should be receiving the equivalent of 8 to 24 mg of buprenorphine daily. One Suboxone® (buprenorphine and naloxone) 8 mg/2 mg sublingual tablet provides equivalent buprenorphine exposure to one Subutex® (buprenorphine HCl) 8 mg sublingual tablet or one Bunavail® (buprenorphine and naloxone) 4.2 mg/0.7 mg buccal film or one Zubsolv® (buprenorphine and naloxone) 5.7 mg/1.4 mg sublingual tablet.
• Dosing: 300 mg monthly for the first two months, followed by a maintenance dose of 100 mg monthly
• Maintenance dose may be increased to 300 mg monthly for patients who tolerate the 100 mg dose but do not demonstrate a satisfactory clinical response
• There should be a minimum of 26 days between doses
• For abdominal subcutaneous administration only. Should only be administered by a healthcare provider.
• Missed doses: A patient who misses a dose should receive the next dose as soon as possible, with the following dose given no less than 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect.
• For patients in established treatment of 100 mg monthly, there may be instances when allowance for a two-month dosing interval may be appropriate (e.g., extended travel); in those instances, a single 300 mg dose may be given to cover a two-month period. Thereafter, the 100 mg monthly regimen would resume. Patients should be cautioned that the peak plasma level after injection of a 300 mg dose will be higher than their usual monthly dose and that they may experience sedation or other buprenorphine related effects
• Subclocade is injected as a liquid, and the subsequent precipitation of the poly polymer creates a solid depot that contains buprenorphine. The depot disintegrates over time but may be surgically excised under local anesthesia within 14 days of injection.
• After steady-state has been achieved (4-6 months), patients discontinuing Sublocade may have detectable plasma levels of buprenorphine for twelve months or longer [7]

• Pharmacology
• Buprenorphine is a partial opioid mu receptor agonist, which means it stimulates opioid receptors to a degree, but unlike full agonists, it has a ceiling effect. Buprenorphine binds opioid receptors tightly and disassociates slowly; this can cause it to displace full agonists (e.g. heroin, morphine) from the receptors and precipitate withdrawal. When absorbed intestinally, buprenorphine is rapidly metabolized in the liver via the first-pass effect. Because of this, it is only available in sublingual and buccal forms.

• Pharmacokinetics
• Onset of action: peak effect in 100 minutes
• Half-life: 24 - 42 hours

• Prescribing requirements
• Providers must obtain a waiver and, in some cases, undergo special training in order to prescribe buprenorphine for OUD. See SAMHSA website for details

• Prescribing documents
• Several documents that may be helpful for buprenorphine prescribing are provided below


• Buprenorphine treatment agreement - document for patients to sign that outlines treatment expectations and buprenorphine precautions
• Buprenorphine induction - document that explains buprenorphine induction to patients


• The PCSS also publishes buprenorphine prescribing documents. See PCSS clinical tools for more.

• Reference: Subutex PI

Buprenorphine side effects in a 4-week study
Side effect	Subutex 16 mg (N=103)	Placebo (N=107)
Headache	29.1%	22.4%
Insomnia	21.4%	15.9%
Withdrawal syndrome	18.4%	37.4%
Pain	18.4%	18.7%
Nausea	13.6%	11.2%
Sweating	12.6%	10.3%
Pain Abdomen	11.7%	6.5%
Infection	11.7%	6.5%
Rhinitis	9.7%	13.1%
Chills	7.8%	7.5%
Pain Back	7.8%	11.2%
Constipation	7.8%	2.8%
Vomiting	7.8%	4.7%
Asthenia	4.9%	6.5%
Diarrhea	4.9%	15.0%
Vasodilation	3.9%	6.5%

• Contraindications / Precautions
• Drug addiction and abuse - opiates are both physically and psychologically addictive. Use caution in susceptible patients.


• Respiratory depression and death - there have been cases of respiratory depression leading to death in patients receiving buprenorphine. Most cases involved misuse by self-injection or concomitant use of benzodiazepines or other CNS depressants, including alcohol.


• Central sleep apnea - opiates can cause or worsen central sleep apnea. Use caution in susceptible patients.


• Pulmonary disease - opiates suppress respiratory drive and may lead to hypoxia and even death in patients with respiratory disease. Use caution in susceptible patients.


• Intestinal disorders - opiates inhibit bowel peristalsis and can worsen some bowel conditions. Use caution in patients with intestinal disorders.


• Withdrawal syndrome - abruptly stopping opiates after chronic therapy may lead to withdrawal reactions, including diarrhea, nausea and vomiting, confusion, somnolence, visual hallucinations, and dysphoria. Taper dose slowly depending on the situation and medication.


• Adrenal insufficiency - cases of adrenal insufficiency have been reported with opiate use. Most cases occurred after more than 1 month of therapy. Adrenal insufficiency may present as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is diagnosed, treat with corticosteroids and wean the patient off their opiate. After adrenal function returns, other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.


• Opiate-naïve patients - there have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine sublingual tablets are not appropriate as an analgesic.


• Head injury and increased intracranial pressure - use caution in patients with head injuries or increased intracranial pressure. Opiates may suppress respiratory drive causing CO₂ retention, which increases intracranial pressure.


• Elderly patients - elderly patients are more susceptible to the side effects of opiates. Use caution.


• Hypotension - opiates may cause severe hypotension. Use caution in susceptible patients (e.g. dehydration, heart disease, elderly).


• Pregnancy - prolonged use of opioids in pregnancy can lead to neonatal opioid withdrawal syndrome, which can be life-threatening


• Seizure disorders - opiates may lower the seizure threshold and increase the risk of seizures


• Biliary disease - opiates may cause spasms of the sphincter of Oddi. Use caution in patients with biliary disease or pancreatitis.


• Hypersensitivity reactions - hypersensitivity reactions, including anaphylaxis, have been reported with buprenorphine. Common reactions include rashes, hives, and pruritus. Buprenorphine is contraindicated in patients with a history of significant reactions.


• Dental problems (products that dissolve in the mouth) - dental problems, including tooth decay, cavities, dental abscesses/infection, tooth erosion, and tooth loss, have been reported in patients using buprenorphine medications that dissolve in the mouth. Problems have occurred in patients with no prior history of dental issues. Measures that may help prevent problems include taking a large sip of water after the product fully dissolves, swishing it gently around the teeth and gums, and swallowing it. Patients should also wait at least one hour before brushing their teeth after using the product. Regular visits to a dentist are also recommended.


• Hepatotoxicity - buprenorphine has been associated with cases of liver toxicity ranging from mild enzyme elevations to hepatic failure. Patients with pre-existing liver disease (e.g. alcoholism, hepatitis C) may be at greater risk. Baseline and periodic LFTs are recommended during therapy.


• Prolonged QT interval - studies have shown that buprenorphine prolongs the QT interval by ≤ 15 msec. This effect is unlikely to be pro-arrhythmic in patients without other risk factors. In patients with risk factors (e.g. hypokalemia, bradycardia, recent conversion from atrial fibrillation, CHF, digitalis therapy, congenital long QT syndrome, hypomagnesemia), caution should be used. The risk of combining buprenorphine with other QT-prolonging drugs is unknown.


• Kidney disease - has not been studied. Manufacturer makes no recommendation.


• Liver disease
• Child-Pugh A/B: monitor for signs and symptoms of toxicity
• Child-Pugh C: exposure is increased. Consider reducing the dose by half. [7]

• Drug interactions
• Benzodiazepines and other central nervous system (CNS) depressants - opiates may potentiate the effects of benzodiazepines and other CNS depressants (e.g., sedatives, alcohol, neuroleptics). In most cases, these drugs should be discontinued before opiate therapy is begun. If concomitant use is warranted, lowest effective doses should be used, and naloxone for emergency use should be prescribed.


• Gabapentin (Neurontin) and Pregabalin (Lyrica) - gabapentin and pregabalin can enhance the effects of opioids and increase the risk of overdose and death. Avoid concomitant use if possible. [16]


• CYP3A4 inhibitors and inducers - buprenorphine is a CYP3A4 sensitive substrate. CYP3A4 inhibitors may increase buprenorphine exposure, and CYP3A4 inducers may decrease exposure. When combining buprenorphine with an inhibitor, consider reducing the buprenorphine dose and monitoring for toxicity. If an inhibitor is discontinued, the buprenorphine dose may need to be increased. When combining buprenorphine with an inducer, consider increasing the buprenorphine dose and monitoring efficacy. If an inducer is discontinued, the buprenorphine dose may need to be decreased.


• Muscle relaxers - opiates may enhance the neuromuscular blocking action of skeletal muscle relaxants and increase the risk of respiratory depression. Use caution when combining and strongly consider prescribing naloxone for emergency use.


• Anticholinergic medications - opiates may potentiate the urinary retention and constipating effects of anticholinergic medications


• MAO inhibitors - MAO inhibitors may potentiate the effects of opiates and vice versa. Opiates and MAO inhibitors should not be taken within 14 days of each other.


• Tricyclic antidepressants - tricyclic antidepressants may potentiate the effects of opiates and vice versa


• Diuretics - opiates may reduce the efficacy of diuretics by inducing ADH release. Monitor for reduced diuresis and increase the diuretic dose if necessary.


• Serotonergic drugs - opiates may potentiate the effects of serotonergic medications and increase the risk of serotonin syndrome


• Cimetidine (Tagamet®) - cimetidine may potentiate the respiratory depression seen with opiate medications. Use caution. [7]

• Efficacy
• Subutex vs Suboxone vs Placebo for Outpatient Treatment of OUD, NEJM (2003) [PubMed abstract]
• Buprenorphine injection vs Placebo injection for opioid abstinence, Lancet (2019) [PubMed abstract]
• Buprenorphine implant vs Placebo implant for opioid abstinence, JAMA (2016) [PubMed abstract]
• Naltrexone IM vs Buprenorphine to Prevent Opiate Relapse, Lancet (2018) [PubMed abstract]
• Naltrexone IM vs Buprenorphine to Prevent Opiate Relapse, JAMA Psych (2017) [PubMed abstract]

---

• METHADONE (CII)

• Dosage forms
• Tablet
• 5 mg
• 10 mg
• Generic available: $ for 90 tablets
• Dispersible tablet for suspension (Methadose®)
• 40 mg
• Generic available: $ for 35 tablets
• Solution
• 5 mg/5 ml
• 10 mg/5 ml
• Generic available: $-$$ for 480 ml
• Concentrate (Methadose®)
• 10 mg/1 ml
• Generic available: $ for 180 ml

• Dosing
• Acute opiate withdrawal
• See acute withdrawal for recommendations on initiating methadone during opiate withdrawal


• Chronic pain, opiate-naïve (children 1 - 12 years)
• 0.100 mg/kg (max 5 mg/dose) every 6 - 8 hours
• Increase dose every 5 - 7 days [12]
• May also be dosed every 12 hours


• Chronic pain, opiate-naïve (adults)
• 2.5 mg every 8 hours
• Increase dose no more than 5 mg/day every 5 - 7 days [12]
• May also be dosed every 12 hours


• Converting from other opiates to methadone (chronic pain)
• See morphine milligram equivalent table
• Patients taking < 40 – 60 mg/day of morphine or equivalent
• Start methadone 2.5 mg three times a day
• Increase dose no more than 5 mg/day every 5 to 7 days
• Patients taking > 60 mg/day of morphine or equivalent
• Start methadone therapy at a dose 75 to 90% less than the calculated equianalgesic dose and at no higher than 30 to 40 mg/day
• Increases dose no more than 10 mg/day every 5 to 7 days [12]


• Discontinuing methadone (based on PMID 26028120)
• Patients taking > 100 mg/day
• Reduce dose by 5 mg/day down to 100 mg, then reduce by 3 mg/day to 0 mg
• Patients taking ≤ 100 mg/day
• Reduce dose by 3 mg/day down to 0 mg

• Pharmacology
• Methadone is a full opioid agonist. Compared to short-acting opioids, it has a slow onset of action and long duration of effect, which helps to reduce the highs (euphoria) and lows (withdrawal) of opiate abuse.

• Pharmacokinetics
• Onset of action: peak plasma concentrations in 1 to 7.5 hours
• Half-life: 22 - 24 hours on average; up to 59 hours in some people

• Prescribing requirements
• Methadone for OUD is available through clinics that have been accredited and certified by SAMHSA as opioid treatment programs. See SAMHSA website for details.

• Side effects
• Respiratory depression - all opiates can suppress respiratory drive and cause death. Patients and caregivers should be able to recognize symptoms of respiratory depression (e.g. shallow breathing, confusion, decreased alertness, blue skin) and be prepared to call 911 should they occur. Naloxone should also be made available to susceptible patients (see who should carry naloxone).


• Constipation - constipation is a common side effect of opiates that does not typically improve with continued use. A high fiber diet, stool softeners, and laxatives may be helpful in some patients. Peripheral opioid antagonists (methylnaltrexone and naloxegol) may also be used to treat opiate-induced constipation.


• Nausea and vomiting - nausea and vomiting are common side effects of opiates. They typically diminish with continued use.


• Urinary retention - urinary retention from opiates is common and occurs through central and peripheral mechanisms. Naltrexone can be used to reverse opioid-induced urinary retention.


• Pruritus (itching) - opiates can cause itching through a central mu-opioid receptor-mediated mechanism. This is a side effect of opiates and should not be confused with an allergic reaction. The presence of a rash or hives in addition to the itching may indicate a true opiate allergy. Itching can be treated with antihistamines, promethazine, or naloxone in severe cases.


• Mental status changes - delirium, sedation, confusion, and impaired cognitive function may occur with all opiates. Elderly patients may be more susceptible.


• Male hypogonadism - chronic opiate use suppresses GnRH synthesis and may lead to hypogonadism (low testosterone) in males


• Infertility - prolonged opiate use may reduce fertility in males and females. It is unknown if these effects are reversible upon discontinuation.


• Hypotension (low blood pressure) - opiates may lower blood pressure in some patients. Use caution in susceptible patients (e.g. dehydration, elderly). [7]

• Contraindications / Precautions
• Prolonged QT interval - methadone can prolong the QT interval and cause serious arrhythmias that lead to death. Most cases have occurred in patients receiving high doses (> 200 mg/day) for chronic pain, but at-risk patients may be affected at lower doses. The ASAM recommends that patients be screened for heart disease and risk factors (e.g. family history of sudden cardiac death, unexplained syncope, QT-prolonging meds, hypokalemia, hypomagnesemia) before use. Patients with significant risk factors should have an ECG at baseline, 30 days after initiation, and yearly thereafter. If QT_c is 450 - 500 ms, the risks and benefits of methadone should be discussed. If QT_c is > 500 ms, methadone should not be started, and patients who are already receiving therapy should consider lowering the dose and/or switching to buprenorphine. [2]


• Drug addiction and abuse - opiates are both physically and psychologically addictive. Use caution in susceptible patients.


• Central sleep apnea - opiates can cause or worsen central sleep apnea. Use caution in susceptible patients.


• Pulmonary disease - opiates suppress respiratory drive and may lead to hypoxia and even death in patients with respiratory disease. Use caution in susceptible patients.


• Intestinal disorders - opiates inhibit bowel peristalsis and can worsen some bowel conditions. Use caution in patients with intestinal disorders.


• Withdrawal syndrome - abruptly stopping opiates after chronic therapy may lead to withdrawal reactions, including diarrhea, nausea and vomiting, confusion, somnolence, visual hallucinations, and dysphoria. Taper doses slowly when discontinuing after chronic use.


• Adrenal insufficiency - cases of adrenal insufficiency have been reported with opiate use. Most cases occurred after more than 1 month of therapy. Adrenal insufficiency may present as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is diagnosed, treat with corticosteroids and wean the patient off their opiate. After adrenal function returns, other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.


• Head injury and increased intracranial pressure - use caution in patients with head injuries or increased intracranial pressure. Opiates may suppress respiratory drive causing CO₂ retention, which increases intracranial pressure.


• Elderly patients - elderly patients are more susceptible to the side effects of opiates. Use caution.


• Pregnancy - prolonged use of opioids in pregnancy can lead to neonatal opioid withdrawal syndrome, which can be life-threatening


• Seizure disorders - opiates may lower the seizure threshold and increase the risk of seizures


• Biliary disease - opiates may cause spasms of the sphincter of Oddi. Use caution in patients with biliary disease or pancreatitis.


• Kidney disease - has not been studied. Unmetabolized methadone and its metabolites are excreted in the urine to a variable degree. Start patients with kidney disease on lower doses and use longer dosing intervals. Titrate slowly.


• Liver disease - has not been studied extensively. Methadone is metabolized in the liver, and exposure is likely increased in liver disease. Start patients on lower doses and use longer dosing intervals. Titrate slowly. [7]

• Drug interactions
• Benzodiazepines and other central nervous system (CNS) depressants - opiates may potentiate the effects of benzodiazepines and other CNS depressants (e.g., sedatives, alcohol, neuroleptics). In most cases, these drugs should be discontinued before opiate therapy is begun. If concomitant use is warranted, lowest effective doses should be used, and naloxone for emergency use should be prescribed.


• Cytochrome P450 enzymes - methadone is metabolized by the CYP enzymes listed below. Inhibitors of these enzymes may increase methadone exposure, and inducers may decrease exposure. When combining methadone with an inhibitor, consider reducing the methadone dose and monitoring for toxicity. If an inhibitor is discontinued, the methadone dose may need to be increased. When combining methadone with an inducer, consider increasing the methadone dose and monitoring for withdrawal. If an inducer is discontinued, the methadone dose may need to be decreased.
• CYP3A4
• CYP2B6
• CYP2C19
• CYP2C9
• CYP2D6


• Antiretrovirals - certain protease inhibitors with CYP3A4 inhibitory activity (e.g. abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir) have paradoxically caused decreased methadone exposure. Monitor patients for withdrawal symptoms when combining.


• QT-prolonging drugs - methadone can prolong the QT interval, and the risk may be enhanced when given with other QT-prolonging drugs. Avoid concomitant use or monitor patients closely if combining. See prolonged QT interval above for more.


• Drugs that cause hypokalemia or hypomagnesemia - hypokalemia and hypomagnesemia can increase the risk of QT prolongation, and therefore, medications that promote these electrolyte disturbances may also increase the risk. See hypokalemia causes and hypomagnesemia causes for more.


• Muscle relaxers - opiates may enhance the neuromuscular blocking action of skeletal muscle relaxants and increase the risk of respiratory depression. Use caution when combining and strongly consider prescribing naloxone for emergency use.


• Anticholinergic medications - opiates may potentiate the urinary retention and constipating effects of anticholinergic medications


• MAO inhibitors - MAO inhibitors may potentiate the effects of opiates and vice versa. Opiates and MAO inhibitors should not be taken within 14 days of each other.


• Tricyclic antidepressants - tricyclic antidepressants may potentiate the effects of opiates and vice versa


• Diuretics - opiates may reduce the efficacy of diuretics by inducing ADH release. Monitor for reduced diuresis and increase the diuretic dose if necessary.


• Serotonergic drugs - opiates may potentiate the effects of serotonergic medications and increase the risk of serotonin syndrome


• Didanosine and Stavudine - methadone may decrease didanosine and stavudine exposure


• Zidovudine - methadone may increase zidovudine exposure, which can lead to toxicity


• Desipramine - methadone may increase desipramine exposure


• Cimetidine (Tagamet®) - cimetidine may potentiate the respiratory depression seen with opiate medications. Use caution. [7]

---

• NALTREXONE

• Dosage forms
• Tablet (Revia®)
• 50 mg
• Generic available: $ for 30 tablets
• Injection (Vivitrol®)
• 380 mg vial
• Carton comes with vial, diluent, special needle, and syringe
• No generic: $$$$ for 1 vial
• Keep refrigerated. Good for 7 days at room temp.

• Dosing
• In general, at least 6 opioid-free days should pass before initiating naltrexone in patients who are stopping short-acting opioids, and 7 - 10 days should pass for long-acting opioids like methadone and buprenorphine. In cases where it is unknown if withdrawal is complete, a naloxone challenge may be performed.
• Tablet (daily): 50 mg once daily
• Tablet (three times a week): three doses a week with two 100-mg doses followed by one 150-mg dose
• Injection: 380 mg intramuscularly every 4 weeks. Dose should only be given as a deep intramuscular gluteal injection administered by a healthcare provider. Alternate buttocks with each injection. [7]

• Pharmacology
• Naltrexone is an opioid antagonist that binds to opioid receptors and blocks the effects of opiates. Naltrexone should only be initiated in patients who are past the withdrawal phase of opiate abuse because it can worsen withdrawal symptoms. In general, at least 6 opioid-free days should pass before initiating naltrexone in patients who are stopping short-acting opioids, and 7 - 10 days should pass for long-acting opioids like methadone and buprenorphine.

• Side effects
• The table below shows the incidence of side effects from an OUD trial involving naltrexone 380 mg IM every 4 weeks. Only side effects that occurred at an overall incidence of ≥ 2% and more than placebo are listed.

• Reference [7]

Side effect	Naltrexone 380 mg (N=126)	Placebo (N=124)
ALT increase	13%	6%
AST increase	10%	2%
GGT increase	7%	3%
Nasopharyngitis	7%	2%
Influenza	5%	4%
Insomnia	6%	1%
Hypertension	5%	3%
Injection site pain	5%	1%
Toothache	4%	2%
Headache	3%	2%

• Contraindications / Precautions
• Patients receiving opioids - naltrexone is an opioid antagonist, and it will block the effects of opioid medications. It should not be given to patients who are receiving opioids or those going through acute opioid withdrawal.


• Precipitated opioid withdrawal - naltrexone may precipitate opioid withdrawal in patients receiving opioids. Naltrexone-induced withdrawal typically occurs within 5 minutes of ingestion and lasts up to 48 hours. Symptoms may be more severe than what is seen with typical opioid discontinuation, and patients may need to be hospitalized. Opioid-dependent patients taking short-acting opioids should be opioid-free for 6 - 10 days before starting naltrexone, and those taking buprenorphine or methadone may experience naltrexone-induced withdrawal for up to 2 weeks after opioid discontinuation.


• Increased sensitivity to opioids - patients who have received naltrexone for a period and then discontinue it may be more sensitive to opioid medications. These patients should be warned that they may be at increased risk of an overdose if they take opioids after stopping naltrexone. Naloxone should be offered to these patients.


• Overcoming naltrexone blockade - naltrexone blockade of opioid receptors is competitive and can be overcome by high plasma concentrations of opioids. Patients who try to overcome naltrexone by taking large doses of opioids are at increased risk of overdose. Patients should be warned that they may experience fatal overdose should they try to overcome naltrexone blockade.


• Emergency pain control - emergency pain control in patients taking naltrexone may be achieved through regional analgesia, conscious sedation with a benzodiazepine, non-opioid analgesics, or general anesthesia. In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. See treating acute pain.


• Hepatotoxicity - cases of hepatitis have been reported in patients receiving naltrexone. Since patients receiving naltrexone often have pre-existing liver disease, it is difficult to establish causality. Patients who experience symptoms of hepatitis during naltrexone therapy (e.g. jaundice, nausea, vomiting, dark urine, abdominal pain) should stop naltrexone and receive prompt evaluation.


• Depression and suicidality - depression and suicidality in patients receiving naltrexone have been reported in the postmarketing setting. Patients being treated for opioid and alcohol abuse often have coexisting depression, so it is difficult to establish causality. Patients who experience depressive symptoms while taking naltrexone should report them immediately.


• Drug testing - naltrexone may cause some urine drug screens to show a positive opioid result. Naltrexone hydrochloride does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used to separate and detect morphine, methadone, or quinine in the urine. Naltrexone hydrochloride may or may not interfere with enzymatic methods for detecting opioids, depending on the specificity of the test. Please consult the test manufacturer for specific details.


• Eosinophilic pneumonia (IM naltrexone) - rare cases of eosinophilic pneumonia have been reported in patients receiving IM naltrexone (Vivitrol). If a patient develops progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered.


• Hypersensitivity reactions (IM naltrexone) - hypersensitivity reactions including urticaria, angioedema, and anaphylaxis have been reported in patients receiving IM naltrexone (Vivitrol)


• Injection site reactions (IM naltrexone) - injection site reactions, including tenderness, pain, and swelling, are common with IM naltrexone. Rare cases of cellulitis, abscess, and necrosis requiring surgery, have been reported. IM naltrexone should only be administered by a healthcare professional.


• Kidney disease
• CrCl ≥ 50 ml/min: no dose adjustment necessary
• CrCl < 50 ml/min: has not been studied. Because naltrexone and its primary metabolite are excreted in the urine, caution is recommended.


• Liver disease
• Child-Pugh A/B: no dose adjustment necessary
• Child-Pugh C: has not been studied. Use caution. [7]

• Drug interactions
• Opiate medications - naltrexone may block the effects of opioid medications, including dextromethorphan and antidiarrheals. See Precautions above. [7]

• Effectiveness
• Naltrexone IM vs Buprenorphine to Prevent Opiate Relapse, Lancet (2018) [PubMed abstract]
• Naltrexone IM vs Buprenorphine to Prevent Opiate Relapse, JAMA Psych (2017) [PubMed abstract]
• Vivitrol vs Usual Care to Prevent Opiate Relapse, NEJM (2016) [PubMed abstract]

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• NALOXONE

• Overview
• Naloxone is an opioid antagonist that blocks opioid receptors and reverses the effects of opiates. It has a rapid onset of action, which makes it ideal for treating opioid overdose. Naloxone is also included in certain buprenorphine products (e.g. Suboxone). When the products are taken as instructed, the naloxone is only minimally absorbed and has no meaningful effect. If the products are injected, the naloxone will precipitate withdrawal.
• It is recommended that all patients being treated for OUD have naloxone available in case of an emergency (see who should carry naloxone). In most states, pharmacists can dispense naloxone without a prescription.

• Naloxone products
• Evzio® auto-injector - inject SQ or IM in the thigh. When activated, gives voice instructions. Generic available: $$$ for 2 auto-injectors.
• Zimhi® prefilled syringe - inject SQ or IM in the thigh. No generic: $$$ for 2 syringes.
• Narcan® nasal spray - spray into the nostril. Generic available: $-$$ for 2 sprays.
• Kloxxado® nasal spray - spray into the nostril. No generic: $$$ for 2 sprays.
• Naloxone vial and prefilled syringe - may be given IM, SQ, or IV. Primarily intended for medical personnel. Generic available: $ for 1 vial/syringe.

• Naloxone challenge
• When initiating naltrexone, it's important that the patient is past the withdrawal phase, or naltrexone may precipitate withdrawal symptoms that last for days. One way to see if patients are ready for naltrexone is to perform a naloxone challenge test. Naloxone has a rapid onset and short duration of action, and small doses can be used to test for incomplete withdrawal.
• Naloxone challenge test
• Administer 0.8 mg of naloxone subcutaneously. Alternatively, the dose may be split in two with an initial 0.4 mg dose that is followed by another 0.4 mg dose if no withdrawal occurs.
• Naloxone will precipitate withdrawal symptoms within 5 - 10 minutes in patients who are still dependent. Symptoms typically dissipate within 30 minutes.
• If no symptoms occur, the patient may start naltrexone. If symptoms occur, naltrexone should be held, and the test should be repeated in 24 hours. [7]

• Who should carry naloxone
• The U.S. Department of Health and Human Services recommends patients who meet any of the criteria below be prescribed naloxone injection or nasal spray for use in cases of accidental overdose


• Patients Prescribed Opioids Who:
• Are receiving opioids at a dosage of 50 morphine milligram equivalents (MME) per day or greater (see morphine milligram equivalent table)
• Have respiratory conditions such as chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (regardless of opioid dose)
• Have been prescribed benzodiazepines (regardless of opioid dose)
• Have a non-opioid substance use disorder, report excessive alcohol use, or have a mental health disorder (regardless of opioid dose)


• Patients at high risk for experiencing or responding to an opioid overdose, including individuals:
• Using heroin, illicit synthetic opioids, or misusing prescription opioids
• Using other illicit drugs such as stimulants, including methamphetamine and cocaine, which could potentially be contaminated with illicit synthetic opioids like fentanyl
• Receiving treatment for opioid use disorder, including medication-assisted treatment with methadone, buprenorphine, or naltrexone
• With a history of opioid misuse that were recently released from incarceration or other controlled settings where tolerance to opioids has been lost [10]

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• PREGNANCY

• Overview
• Infants born to women who use opioids, including buprenorphine and methadone, are at risk for neonatal abstinence syndrome (NAS), which is characterized by irritability, tremors, tachypnea, nasal congestion, diarrhea, feeding difficulties, weight loss, seizures, and even death.
• Buprenorphine and methadone have been studied in pregnancy and are used to treat OUD in this population. Information on naloxone-containing buprenorphine products (e.g. Suboxone) is not as extensive, but limited data indicates they are safe, and the ASAM guidelines state that they may be used.
• Naltrexone has insufficient pregnancy data, and the ASAM recommends one of the following in women who become pregnant while taking it: (1) stop naltrexone if the risk of relapse is low, (2) transition to buprenorphine or methadone, (3) continue naltrexone with the understanding that the potential risks are unknown.


• Studies
• A small randomized controlled trial (N=175) compared methadone to buprenorphine in pregnant women with OUD. The primary outcomes were number of neonates requiring treatment for NAS, peak NAS score, total amount of morphine needed to treat NAS, length of neonatal hospital stay, and head circumference. At the end of the study, 47% of infants in the buprenorphine group required NAS treatment compared to 57% in the methadone group (p=0.26). Buprenorphine was superior to methadone for morphine required (mean dose, 1.1 mg vs. 10.4 mg; p<0.0091), neonatal hospital stay (10.0 days vs. 17.5 days, p<<0.0091), and NAS treatment duration (4.1 days vs. 9.9 days, p<0.0031). [PMID 21142534]
• A cohort study published in 2022 compared the risk of adverse neonatal outcomes between buprenorphine and methadone in pregnant women treated for OUD. NAS occurred in 52% of infants in the buprenorphine group and 69% in the methadone group (HR 0.73, 95%CI [0.71 - 0.75]). Other outcomes favored buprenorphine, including preterm birth (14.4% vs 24.9%), small for gestational age (12.1% vs 15.3%), and low birth weight (8.3% vs 14.9%). [PMID 36449419]


• Professional recommendations
• ASAM guidelines for treating OUD in pregnancy are available at the link below
• ASAM 2020 OUD Guidelines - pregnancy recommendations start on page 50

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• OPIOID TAPERING RECOMMENDATIONS

• Overview
• In 2016, the U.S. Veterans Administration issued broad recommendations for tapering opiates in order to avoid withdrawal symptoms and rebound pain. Those guidelines are summarized below.


• Slowest taper - Consider for patients taking high doses of long-acting opiates for many years
• Reduce dose by 2 - 10% every 4 - 8 weeks with pauses in taper as needed


• Slower taper - Appropriate for most patients
• Reduce dose by 5 - 20% every 4 weeks with pauses in taper as needed


• Faster taper - May cause withdrawal symptoms that need to be treated
• Reduce dose by 10 - 20% every week


• Fastest taper - May cause withdrawal symptoms that need to be treated
• Reduce dose by 20 - 50% on first day, then reduce dose by 10 - 20% every day [6]

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• 1 - CDC website
• 2 - PMID 32511106 - The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update, J Addict Med (2020)
• 3 - PMID 32563380 - New directions in the treatment of opioid withdrawal, Lancet (2020)
• 4 - PMID 31536249 - Dhaliwal A, Gupta M. Physiology, Opioid Receptor. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
• 5 - PMID 27464203 - Treatment of Opioid-Use Disorders, NEJM (2016)
• 6 - Pain Management Opioid Taper Decision Tool: A VA Clinician's Guide, (2016)
• 7 - Manufacturer's prescribing information
• 8 - PMID 28557958 - Appropriate Use of Drug Testing in Clinical Addiction Medicine, J Addict Med (2017)
• 9 - PMID 24986836 - False-positive interferences of common urine drug screen immunoassays: a review, J Anal Toxicol (2014)
• 10 - PMID 34751711 - Higher-Dose Naloxone Nasal Spray (Kloxxado) for Opioid Overdose, JAMA (2021)
• 11 - PMID 29114811 - Interpretation of Urine Drug Screens: Metabolites and Impurities, JAMA (2017)
• 12 - PMID 24685458 - Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, J Pain (2014)
• 13 - Health Resources & Services Administration website
• 14 - PMID 28325505 - Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens, Mayo Clin Proc (2017)
• 15 - PMID 20412503 - The role of urine drug testing for patients on opioid therapy, Pain Pract (2010)
• 16 - PMID 35762989 - Gabapentin Increasingly Implicated in Overdose Deaths, JAMA (2022)