CONTENTS

• Signs & symptoms of opioid withdrawal
• DSM-5 criteria for opioid use disorder
• Recommended diagnostic testing
• Selection of buprenorphine vs. methadone vs. short-acting opioids
• BUPRENORPHINE
  • Buprenorphine basics
  • Induction
    • Traditional induction
    • Induction via MACROdosing
    • Induction via MICROdoses
  • Buprenorphine precipitated withdrawal
• Methadone
• Adjunctive therapies for opioid withdrawal
• Acute pain in a patient on chronic buprenorphine or methadone
• Opioid use disorder & pregnancy

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opioid withdrawal

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timing

• See the table below.
• However, fentanyl may have a slower withdrawal onset (e.g., ~8-24 hours). (38683591) Ongoing fentanyl use may cause fentanyl to be adsorbed into the fat tissue, causing its half-life to extend (exactly the same as with a continuous fentanyl infusion).  

clinical features

• Psychiatric:
  • Irritability, restlessness, anxiety, insomnia.
  • Pain (e.g., back pain).
  • Depression.
• Sympathetic activation:
  • Diaphoresis.
  • Tremor.
  • Pupillary dilation.
  • Tachycardia.
  • Hypertension.
  • Hyperthermia.
• Secretions:
  • Lacrimation.
  • Rhinorrhea.
  • Nausea, vomiting, diarrhea, and abdominal cramping.
• Miscellaneous:
  • Yawning.
  • Piloerection. (38683591)

COWS (clinical opiate withdrawal scale)

The COWS score should be at least ≧8 when initiating a standard buprenorphine induction, but it might be ideal for the COWS score to be >12. 

• 🐄 Heart rate:
  • 0 pulse rate ≦80
  • 1 pulse rate 81-1 00
  • 2 pulse rate 101-120
  • 4 pulse rate >120
• 🐄 Sweating:
  • 0 no report of chills or flushing
  • 1 subjective report of chills or flushing
  • 2 flushed or observable moistness on face
  • 3 beads of sweat on brow or face
  • 4 sweat streaming off face
• 🐄 Restlessness:
  • 0 able to sit still
  • 1 reports difficulty sitting still, but can do so
  • 3 frequent shifting or extraneous movements of legs/arms
  • 5 unable to sit still for more than a few seconds
• 🐄 Pupil size:
  • 0 pupils pinned or normal size for room light
  • 1 pupils possibly larger than normal for room light
  • 2 pupils moderately dilated
  • 5 pupils so dilated that only the rim of the iris is visible
• 🐄 Bone or joint aches (not otherwise attritubate to alternative cause):
  • 0 not present
  • 1 mild diffuse discomfort
  • 2 patient reports severe diffuse aching of joints/muscles
  • 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort
• 🐄 Runny nose or tearing:
  • 0 not present
  • 1 nasal stuffiness or unusually moist eyes
  • 2 nose running or tearing
  • 4 nose constantly running or tears streaming down cheeks
• 🐄 GI upset:
  • 0 no GI symptoms
  • 1 stomach cramps
  • 2 nausea or loose stool
  • 3 vomiting or diarrhea
  • 5 multiple episodes of diarrhea or vomiting
• 🐄 Tremor:
  • 0 no tremor
  • 1 tremor can be felt, but not observed
  • 2 slight tremor observable
  • 4 gross tremor or muscle twitching
• 🐄 Yawning:
  • 0 no yawning
  • 1 yawning once or twice during assessment
  • 2 yawning three or more times during assessment
  • 4 yawning several times/minute
• 🐄 Anxiety or irritability:
  • 0 none
  • 1 patient reports increasing irritability or anxiousness
  • 2 patient obviously irritable or anxious
  • 4 patient so irritable or anxious that participation in the assessment is difficult
• 🐄 Piloerection (gooseflesh skin):
  • 0 skin is smooth
  • 3 piloerrection of skin can be felt or hairs standing up on arms
  • 5 prominent piloerrection

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DSM-5 criteria for opioid use disorder

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criteria

• 1. Opioids are often taken in larger amounts or over a longer period than was intended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
• 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.
• 4. Craving, or a strong desire or urge to use opioids.
• 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.
• 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
• 7. Important social, occupational, or recreational activities are given up or reduced because of opioid
  use.
• 8. Recurrent opioid use in situations in which it is physically hazardous.
• 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
• 10. Tolerance, as defined by either of the following:
  • a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect.
  • b. A markedly diminished effect with continued use of the same amount of an opioid.
  • Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision.
• 11. Withdrawal, as manifested by either of the following:
  • a. The characteristic opioid withdrawal syndrome (refer to Criteria A and B of the criteria set for opioid withdrawal).
  • b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms.

interpretation

• OUD is diagnosed when a patient meets two or more criteria within a 12-month period.
• Severity of OUD:
  • 2-3: mild.
  • 4-5: moderate.
  • ≧6: severe.

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recommended diagnostic testing for people with OUD

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This is especially relevant for patients with IV drug use or who engage in transactional sex work: (35880813)

• HIV.
• HBV (nonimmune people should be vaccinated).
• HCV.
• Syphilis serology.
• Urine drug analysis.
• Pregnancy test.

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selection of buprenorphine versus methadone versus short-acting opioids

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best options: buprenorphine versus methadone

basics

• Buprenorphine or methadone are both front-line medications to stabilize opioid withdrawal and treat OUD.
• Admitted patients may be started on therapy regardless of intention to continue taking treatment after discharge (to allow for stabilization). (38683591)
• For patients with numerous simultaneous withdrawal syndromes (e.g., opioids and alcohol), opioid withdrawal should probably be treated with methadone or buprenorphine. (38683591) However, in highly complex patients who are at risk of over-sedation, PRN short-acting opioids may be safer.
• Patient preference and prior experiences may guide selection. Ultimately, the best therapy is whatever treatment the patient will adhere to.  

contraindications/drawbacks to buprenorphine

• [1] Risk of precipitated withdrawal (but this may now be avoided with microinduction).
• [2] CYP 3A4 drug-drug interactions. This usually isn't a huge problem. Given buprenorphine's ceiling effect on respiratory suppression, elevations in buprenorphine level by CYP3A4 inhibitors are less likely to cause harm. CYP3A4 induction may risk decreasing buprenorphine levels, leading to opioid withdrawal. CYP3A4 interactions are discussed here: 📖.
• [3] Acute, severe, uncontrolled pain. Start by first controlling the patient's pain, then later on buprenorphine microinduction may be performed.
• [4] Hepatic failure. This may increase exposure to naloxone, due to impaired metabolism, so combination buprenorphine-naloxone products may be contraindicated. (37979138)

contraindications/drawbacks to methadone

• [1] QT prolongation & Torsade de Pointes:
  • Methadone initiation:
    • QTc >500 ms is an absolute contraindication to methadone initiation.
    • QTc >460 in men or >470 in women is a relative contraindication to methadone initiation.
    • In some cases, QT reduction can be achieved by stopping other QT-prolonging drugs.
  • Methadone continuation: This is more nuanced. For patients with asymptomatic, mild QT prolongation, it's often reasonable to continue methadone (while addressing electrolyte issues and avoiding other QT-prolonging medications). Untreated OUD has high morbidity and mortality, so the risk/benefit ratio may favor methadone continuation. (37898187)
  • History of torsade de pointes: contraindication.
• [2] Risk of respiratory suppression. Avoid methadone in:
  • Patients with a higher risk of sedation (e.g., requiring GABA agonists for alcohol withdrawal).
  • Patients with low opioid tolerance (e.g., patients taking low doses of opioids orally).
  • History of pulmonary disease (especially with chronic hypercapnia).
  • Obstructive sleep apnea.
• [3] CYP drug-drug interactions.  This is more problematic with methadone, given its steeper dose-response curve as compared to buprenorphine and lack of ceiling effect on respiratory suppression.
• [4] Risk of serotonin syndrome (methadone inhibits serotonin reuptake). (34775634) This relative contraindication can generally be resolved by avoiding other serotonergic medications.  
• [5] Inadequate access to outpatient methadone clinics:
  • This is a huge limitation of methadone overall (especially in rural and underserved communities). (35837678)
  • For patients who refuse buprenorphine therapy, inpatient methadone may be utilized even if there isn't a pre-defined discharge strategy. This isn't perfect, but it's better than using shorter-acting opioids (as discussed in the subsection below).
• [6] Profound hepatic failure (although methadone seems to be metabolized normally in cirrhosis). (34775634)

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undesirable: short-acting opioids

• Some patients with OUD will present to the hospital for another problem (e.g., endocarditis) and have no intention of stopping opioid use.
• If the patient declines buprenorphine or methadone therapy, then they may be treated with shorter-acting full opioid agonists to prevent withdrawal (e.g., IV morphine or oral morphine IR as needed). Over time, the morphine requirements may be determined and transitioned to longer-acting oral opioids (e.g., oral morphine extended release).  Adjunctive non-opioid therapies should be utilized to improve symptoms while reducing the opioid requirement (adjuncts discussed below ⚡️).
• The primary goal is to keep the patient comfortable so that they can receive life-saving medical therapy without leaving against medical advice. Over time, ongoing discussions should be pursued regarding the management of OUD. Once patients feel comfortable and safe, they may be more receptive to OUD therapy.

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buprenorphine basics

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contraindications, drug interactions, side effects 👎

contraindications/drawbacks to buprenorphine ⚡️

comment on risk of respiratory suppression with buprenorphine 

• Buprenorphine is a partial agonist, which by itself appears unable to cause respiratory arrest. Overall, buprenorphine is vastly safer than most other opioids (which are full-strength mu-agonists). For example, buprenorphine may be used intentionally to treat respiratory suppression induced by other opioids.
• Respiratory suppression may occur if buprenorphine is given in combination with other agents (e.g. benzodiazepines).

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indications, advantages 👍

• Buprenorphine is indicated for people with OUD who are interested in therapy (who lack contraindications as listed above).
• Buprenorphine is often a preferred/default agent due to logistic issues:
  • Methadone remains substantially restricted.
  • Many patients are unable to travel daily to a methadone clinic (due to geography or other travel limitations).

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dosing

• Dosing strategies are discussed further below:
  • Traditional buprenorphine induction. ⚡️
  • Buprenorphine induction with microdoses. ⚡️

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pharmacology, mechanism of action

• Absorption:
  • Buprenorphine is generally provided as a sublingual film with 30-50% bioavailability and a peak serum level occurring 40 minutes to 3.5 hours after administration. Variability in absorption may contribute to differential sensitivity to buprenorphine. The tablet or film must be allowed to dissolve fully.
  • Sublingual film may be administered to intubated patients. However, this is poorly studied and may be subject to reduced bioavailability (due to dry mouth or reduced sublingual perfusion). (37979138)
• Distribution:
  • Buprenorphine is lipophilic, with a large V_D (~2.5-3 L/kg). Distribution into adipose tissue may prolong its duration of action.
  • Protein binding is ~95%.
• Metabolism:
  • Buprenorphine is metabolized via CYP3A4 into an active metabolite (norbuprenorphine). Drugs inducing or inhibiting CYP3A4 may affect buprenorphine levels (listed here 📖). Norbuprenorphine has little analgesic effect, but it may have greater respiratory depression potential.
  • Both buprenorphine and norbuprenorphine may undergo glucuronidation to form inactive metabolites.
• Elimination:
  • Renal dysfunction:
    • The active metabolite (norbuprenorphine) may accumulate in renal failure. (37979138)
    • Nonetheless, dose adjustment isn’t needed for renal dysfunction. (22809652)
  • The half-life of buprenorphine is ~36 hours (ranging roughly ~24-42 hours). (30500943)
  • The half-life of norbuprenorphine is 22-176 hours. (37898187)
• Mechanism of action:
  • Buprenorphine has a high affinity for the mu opioid receptor, but it is a partial agonist. This makes it a perfect drug to use for opioid use disorder:
    • a) If the patient takes heroin while on buprenorphine, the buprenorphine will tend to block the effect of heroin (thereby affording some protection against respiratory arrest).
    • b) If the patient takes an excessive dose of buprenorphine, they won’t have a respiratory arrest (buprenorphine is a partial agonist, so its respiratory suppressive effects have a ceiling effect at doses >16 mg). (37979138) Interestingly, buprenorphine's analgesic effects don't seem to have a ceiling effect. (37898187)
  • Buprenorphine's antagonism of the kappa opioid receptor and mu opioid receptor may reduce opioid-related adverse effects (e.g., dysphoria, depression, and constipation).  Additionally, inhibition of the kappa opioid receptor may reduce pain hypersensitivity and provide antidepressant properties. (30500943, 38815158)

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traditional buprenorphine induction

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start when the patient is having withdrawal

• Buprenorphine is a partial agonist:
  • If buprenorphine is started while the patient still has a considerable amount of other opioids on board, it may precipitate opioid withdrawal.
  • If buprenorphine is started while the patient has some withdrawal symptoms, the buprenorphine will make the patient feel better.
• Definite opioid withdrawal should be present before starting buprenorphine:
  • [1] COWS score ≧8 (but it might be ideal for COWS to be >12).
  • [2] At least one objective sign of opioid withdrawal. (30616926)
  • If it’s unclear whether the patient is in withdrawal, watchful waiting should reveal this.
• Patients taking longer-acting opioids are at greater risk of induced withdrawal. As a general rule of thumb: (32234267) 📄
  • Patients using short-acting opioids (e.g., heroin) should wait >12 hours since last use.
  • Patients using long-acting opioids (e.g., OxyContin, MS-Contin, fentanyl) should wait >24 hours since last use. Fentanyl is lipophilic, so with repeated use it may accumulate in adipose tissue and function similarly to a long-acting opioid.
  • Patients on methadone should wait >72 hours after last use.
• 🔑 If unsure whether it's too early, consider treating the patient with non-opioid adjunctive therapy and waiting.
  • The longer you can delay the initiation of buprenorphine, the less likely it is that precipitated withdrawal will occur.
  • Adjunctive therapies on board may make the process smoother (especially if mild precipitated withdrawal occurs).
  • (Further discussion of adjunctive therapies below: ⚡️)

day #1

• Buprenorphine has a relatively rapid absorption (1-2 hours) and a long half-life. Therefore, multiple doses will accumulate over time.
• Starting dose:
  • 4 mg is often used (especially for COWS 8-12).
  • 8 mg may be given (especially for COWS >12).
• Evaluate for clinical effect after 60-90 minutes:
  • [1] If there is worsening, see the section below on precipitated withdrawal. ⚡️
  • [2] If there is some clinical improvement, you're on the right track!  This indicates that the likelihood of precipitating withdrawal is low (precipitated withdrawal is most likely with lower doses of buprenorphine, when buprenorphine first starts knocking agonists off the opioid receptors). Additional doses can be administered relatively rapidly to alleviate residual symptoms, typically 8 mg Q1-2hr PRN up to a maximal cumulative dose of ~32 mg if needed. (30616926) Most patients in the pre-fentanyl era achieved complete symptomatic relief at a total dose of ~16 mg. Evidence suggests improved treatment retention with buprenorphine doses of 16-24 mg/day. (35880813)
• If symptoms are markedly improved but not absent despite a moderate/high dose of buprenorphine, consider the addition of adjunctive therapies. ⚡️

subsequent maintenance therapy

• Give the cumulative day #1 dose as a single dose.
• For ongoing withdrawal symptoms, additional buprenorphine may be given.
• Try to keep the cumulative daily dose ≦24 mg if possible. The FDA has recommended against buprenorphine doses over 24 mg. (35837678) This dose ceiling is probably outdated, but nevertheless, doses of >24 mg may require insurance review and cause logistical hangups.

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buprenorphine induction via macrodosing

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concept & evidence behind macrodosing

• By rapidly stimulating a lot of opioid receptors, macrodosing may reduce the likelihood of precipitated withdrawal and quickly cause symptomatic improvement.
• Evidentiary support:
  • [1] Evidence that buprenorphine-induced withdrawal can be treated with additional doses of buprenorphine supports the practice of macrodosing.  If your approach to side effects at an intermediate dose is to give more buprenorphine, then it makes more sense to start with a large dose.
  • [2] A large case series demonstrated favorable results. (34264326)

how is macrodosing performed

• Start with ≧16 mg of buprenorphine.
• Escalate to 16-32 mg over 1-2 initial doses. (38683591)

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buprenorphine induction via microdoses (micro-induction)

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general concept of micro-induction

• Traditional strategies for buprenorphine initiation involve cessation of full agonist use, waiting for opioid withdrawal, and then starting buprenorphine (as described in the above section).
• An alternative strategy is micro-induction.  This involves a gradual and overlapping transition from full agonist to buprenorphine.  The advantage of micro-induction is that it doesn't require going through a period of opioid withdrawal.

candidates for micro-induction: 

• [1] Prerequisites:
  • A patient with OUD admitted to the hospital for another problem. (30387894, 27499655, 30901127) 
  • Anticipated duration of hospitalization is >5 days.
  • Patient is not already withdrawing, with COWS<6. If the patient is already in withdrawal, a standard buprenorphine induction may be easier and faster (as described above). However, in selected cases, withdrawal may be treated with full opioid agonist therapy followed by subsequent buprenorphine microinduction.
• [2] Additional features that suggest benefit from microinduction:
  • Patients with a history of precipitated withdrawal or difficulty starting buprenorphine.
  • Patients requiring opioid analgesics for acute pain.
  • Patients who may not tolerate significant withdrawal.
  • Transitioning to buprenorphine from methadone or fentanyl (which carries a greater risk of precipitated withdrawal). (35880813)

nuts and bolts of micro-induction

• [1] Continue full opioid agonist.
  • Continue the patient on PRN doses of full agonist opioid throughout the micro-induction period.
  • If the patient is on scheduled doses of full agonist, these may also be continued.
• [2] Gradually increase the dose of buprenorphine, for example, as follows. Belbuca™️ is a buprenorphine product for buccal administration that is roughly twice as well absorbed as the usual sublingual buprenorphine/naloxone formulation. If you don't have Belbuca, you can substitute a two-fold higher sublingual buprenorphine dose (i.e., 225 mcg Belbuca™️ = 0.5 mg SL buprenorphine).
  • Step #1:  225 mcg buccal Belbuca™️ q6hrs x3 doses.
  • Step #2: 450 mcg buccal Belbuca™️ q3hrs x6 doses.
  • Step #3: 2 mg sublingual buprenorphone/naloxone q6hr x4 doses.
  • Step #4: 4 mg sublingual buprenorphine/naloxone q6hr x4 doses (for a total of 16 mg).
  • Step #5:
    • Wean off full opioid agonist.
    • Buprenorphine dosing may be consolidated into a once-daily dose (e.g., 16 mg QD). Alternatively, if buprenorphine is being used for OUD and pain management, it may be continued in divided doses.
    • For ongoing pain or cravings, the buprenorphine dose may be increased. However, few patients will require more than 24 mg/day.
• Withdrawal symptoms may occur, but they should be mild. Since the doses of buprenorphine being used are gradually escalated, they shouldn't throw the patient into full withdrawal. Management of withdrawal symptoms may include the following:
  • Symptomatic treatments as needed. ⚡️
  • More gradual dose-escalation of buprenorphine (e.g., cease dose escalation until withdrawal symptoms subside).

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buprenorphine precipitated opioid withdrawal

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epidemiology of precipitated opioid withdrawal

• Risk factors for precipitated opioid withdrawal:
  • Initiation of buprenorphine when COWS score is 8-12.
  • Chronic fentanyl or methadone use (even despite 12-48 hours of abstinence). (38683591)
  • Concurrent benzodiazepine use.
• Protective factors that reduce the likelihood of precipitated withdrawal:
  • No history of prior precipitated withdrawal.
  • History of previously tolerating buprenorphine.
  • Short-acting opioid use (e.g., heroin) >12 hours ago.
  • Primarily using non-parenteral, immediate-release opioids (e.g., oxycodone IR, morphine IR).
  • Extended-release opioids (e.g., oxycodone ER) >24 hours ago. (35623179)

features of precipitated opioid withdrawal

• Symptoms start ~10-15 minutes after administering buprenorphine.
• Symptoms are those of opioid withdrawal (as discussed above).

common differential diagnostic considerations

• Buprenorphine side effects (e.g., nausea, headache, dysphoria). Buprenorphine may be continued, with symptomatic management of side effects.
• Undertreated withdrawal may occur with severe OUD and small starting doses of buprenorphine. This may improve with additional buprenorphine.
• Withdrawal from an additional substance (e.g., alcohol, benzodiazepines, xylazine, GHB).
• Delerium of another etiology.
• Precipitated opioid withdrawal.

management of precipitated opioid withdrawal

• [1] Additional buprenorphine may overcome residual opioids, causing improvement in withdrawal symptoms (up to a cumulative dose of 32 mg). (35623179, 37898187)
• [2] Non-opioid adjunctive therapies may be used to control symptoms (more on adjunctive treatment below: ⚡️).

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methadone

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contraindications, drug interactions, side effects 👎

selection of methadone is discussed above ⚡️

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dosing

dosing for opioid withdrawal: hospital-based rapid titration

• Day #1:
  • Start with 30 mg PO.
  • Then give up to 10 mg q4-6 hours as needed for withdrawal or cravings, typically up to 40 mg total.
  • 🔑 Supplemental short-acting opioids may be used as methadone levels accumulate, especially for patients previously utilizing fentanyl (e.g., oxycodone 10-20 mg titrated to effect). (38683591)
• Day #2:
  • Start with the total day #1 dose in the AM (usually 30-50 mg).
  • Then give up to 10 mg every 4-6 hours as needed for opioid withdrawal or cravings.
  • Typically up to 60 mg total.
• Day #3:
  • Start with the total day #2 dose in the AM (usually 40-60 mg).
  • Then up to 10 mg every 4-6 hours as needed for withdrawal or cravings.
  • Typically up to 70 mg total.
• Day #4 and beyond:
  • Give a total day #3 dose in the AM (usually 50-70 mg).  Hold at this dose for 3 days.  Subsequently, it may increase by 10-20 mg every 3-4 days based on withdrawal and cravings.  (38683591)

chronic maintenance dose

• Doses <30 mg can treat withdrawal, but aren't effective in suppressing cravings.
• Some patients may respond to 30-60 mg/day.
• Most patients have better outcomes with 80-120 mg/day. (35837678, 37898187) Advantages of higher doses include:
  • Effective suppression of cravings.
  • Reduced euphoric response to illicit opioid use superimposed on methadone use.

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monitoring

• [1] Monitor QTc (should remain <460 mg).
  • Avoid QT-prolonging medications.
  • Follow electrolytes, avoid hypokalemia or hypomagnesemia.
• [2] Monitor for respiratory depression.
  • Pay particular attention to clinical status 2-4 hours after receiving a methadone dose, when the drug levels are highest.
• [3] Aggressive bowel regimen, follow for constipation.

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pharmacology, mechanism of action

• Absorption:
  • Oral bioavailability is 36-100% (mean of ~75%).
    • Peak plasma concentration occurs after 1-7.5 hours. Absorption may be slower due to reduced gastric motility caused by opioid effects. Methadone liquid may be absorbed faster than tablets.
    • The peak effect usually occurs after ~3-4 hours. (38683591)
    • Bioavailability varies partially due to first-pass metabolism.
  • IV or IM bioavailability is superior. For patients unable to take enteral methadone, the dose may be converted into an equivalent IV/IM form.
  • PO → IV conversion:
    • Sources vary regarding exactly how to do this. Published references quote the PO:IV ratio varying from 1:1 to 2:1 (thereby approximating the oral bioavailability as ranging between 50% and 100%).
    • Using a 2:1 conversion (dividing the PO dose by 2 to obtain the IV dose) risks underdosing the methadone, since most patients will have bioavailability of >50%. Nonetheless, some authors recommend this as a conservative strategy to avoid toxicity. (37898187)
    • Using a 1:1 conversion may overdose the methadone (since oral bioavailability will invariably be <100%).
    • To convert from PO to IV, it might be most accurate to divide the oral dose by 1.3 (in recognition of the 75% bioavailability). This seems like a reasonable compromise between a 2:1 and a 1:1 conversion. (34775634)
  • Alternative routes of administration aren't great: sublingual (35% absorption) or rectal (35-80% bioavailability).
• Distribution:
  • Methadone is lipophilic with a Vd of 3-8 L/kg.
  • Protein binding is 85-90% (including alpha1-acid glycoprotein).
  • Accumulation in tissues (e.g., liver, lung, adipose) increases the half-life.
  • After ingestion, redistribution into the tissues (alpha-elimination phase) takes ~8-12 hours. (34775634)
• Metabolism:
  • Hepatic metabolism converts methadone into an inactive metabolite via N-demethylation. Various cytochrome enzymes catalyze this:
    • CYP3A4 causes ~60% of methadone metabolism.
    • CYP2B6 metabolizes S-methadone (the less active enantiomer).  Genetic variation in CYP2B6 may affect methadone clearance.
    • Other enzymes involved: CYP 2D6, CYP2C19, CYP2C9.
• Elimination:
  • The terminal half-life is 15-60 hours (mean ~24-36 hours).
  • Due to its lipophilicity, methadone may remain in the tissues for prolonged periods.
  • About 20% of methadone is excreted in the urine (roughly half of which is active). (34775634)
  • There is no need for dose adjustment in renal failure or hemodialysis.
• Mechanism of action:
  • [1] Full mu opioid receptor agonist.
  • [2] Weak NMDA receptor antagonist, which may:
    • May potentiate opioid analgesia.
    • Attenuate hyperalgesia.
    • May possibly limit opioid tolerance. (34775634)
  • [3] Inhibits reuptake of serotonin and norepinephrine.

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adjunctive therapies for opioid withdrawal

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Some patients may have some residual symptoms, which may be treated supportively. 

🏆 alpha-2 agonists

• Use:
  • These may be useful for treating residual symptoms of anxiety, insomnia, and discomfort.
  • Alpha-2 agonists may be especially useful for patients with a component of withdrawal from illicit alpha-2 agonists (xylazine or medetomidine).
• Selection of an agent:
  • Dexmedetomidine 💉 can be up-titrated rapidly to achieve the highest potency.
  • Guanfacine 💉 may be useful to provide sedative effects without causing hypotension (but hypotension is rarely a problem in this patient population).
  • Clonidine 💉 might be the best oral alpha-2 agonist (given greater analgesic efficacy than guanfacine).

antipsychotics (🏆 olanzapine > haloperidol)

• Useful for the treatment of agitation and nausea/vomiting.
• Olanzapine 💉 may have greater antiemetic efficacy due to its activity on 5HT3 receptors.

🏆 ketamine 💉 for analgesia

• [1] Ketamine may help treat acute pain or myalgias caused by opioid withdrawal.
• [2] Ketamine may be especially useful in buprenorphine-induced opioid withdrawal (e.g., at pain doses such as 0.2-0.3 mg/kg). Ketamine exhibits synergistic mu-opioid agonism with buprenorphine, and it may resensitize the cell membrane to increase expression of previously downregulated mu-opioid receptors. (35623179, 34789683)
• [3] Ketamine's antidepressive activities may be helpful. (37898187)

nausea/vomiting

• Olanzapine 💉.
• Ondansetron 💉.
• Prochlorperazine 💉.
• (Further discussion of antiemetics: 📖)

diarrhea

• Loperamide for diarrhea.

analgesics

• Acetaminophen 💉.
• NSAIDs 💉 (if no other organ failures are present).
• Methocarbamol 💉.
• (Ketamine 💉 as above).

anxiolytics

• Hydroxyzine 💉. Use caution, however, since anticholinergic effects may increase the risk of delirium.
• Benzodiazepines 💉 may be helpful for anxiety and nausea/vomiting. However, exercise caution,  since benzodiazepines may cause respiratory suppression when combined with buprenorphine and antipsychotics. (35623179)

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acute pain management in a patient on chronic buprenorphine or methadone

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💡 Sublingual buprenorphine films can and should be given to intubated patients.

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[1/3] what to do with the buprenorphine or methadone

buprenorphine: key physiology

• [1] Buprenorphine is an effective analgesic, with potency roughly thirty times higher than morphine. (30500943)
• [2] Buprenorphine blocks some opioids, but not all:
  • Buprenorphine has a greater affinity for the mu opioid receptor than most opioids (e.g., oxycodone and heroin). Therefore, high-dose buprenorphine (>8-12 mg daily) will block the ability to use most opioids for breakthrough pain. At lower buprenorphine doses, there may be synergistic analgesia between buprenorphine and other opioids. (30500943, 29452378)
  • This has led to concern that giving buprenorphine will make it impossible to treat breakthrough pain, exposing patients to untreatable pain.
  • Fortunately, buprenorphine, hydromorphone, and fentanyl have relatively similar affinities for the mu opioid receptor. Therefore, even in patients receiving high doses of buprenorphine, breakthrough pain can be treated with high doses of hydromorphone or fentanyl. (38815158)

buprenorphine: how to manage it

• Divide the buprenorphine dose into 3-4 daily doses (q6hr-q8hr).
  • For analgesic efficacy, buprenorphine should be given more frequently than daily.
• Should we increase the dose? (especially for patients on <16 mg/day)
  • For patients on ≦16 mg/day buprenorphine, most guidelines recommend continuing the patient's chronic daily dose unchanged (but divided into 3-4 doses). (34775634)
  • However, a moderate dose increase could be considered to improve analgesia (e.g., to 24 mg/day). (37979138)
• Should we decrease the dose? (especially for patients on >16 mg/day)
  • Some authors recommend reducing the buprenorphine dose to 16 mg/day (i.e., 4 mg q6hr).  The rationale is to “open up” some space on the mu receptors, thereby increasing sensitivity to pure opioid agonists. For patients with refractory pain, the buprenorphine dose could be decreased even further below 16 mg/day. (34775634)
  • However, reducing the buprenorphine dose may worsen matters by precipitating opioid withdrawal or cravings. Therefore, decreasing the dose is probably inadvisable. Given the ability of hydromorphone or fentanyl to compete with buprenorphine, these agents should remain effective for breakthrough pain despite buprenorphine use.
• Bottom line: As a general rule of thumb, the patient's chronic dose should be maintained at the same daily dose (but split into q6hr or q8hr doses). Most current guidelines support this middle-of-the-road approach. (38815158)

methadone: continue the same cumulative daily dose

• Continue the patient's chronic methadone dose.
• The methadone dose may be split into q8hr or q12hr to improve analgesic efficacy (due to transiently higher drug levels following each dose, as a result of alpha-elimination). (35880813)

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[#2/3] maximize non-opioid multimodal analgesia

• A multimodal approach combining several non-opioid medications is fundamental. This is often safer and more effective than using high-dose opioids.
• Agents that are often useful include:
  • Scheduled acetaminophen 💉 (e.g., 1 gram orally q6hr).
  • Pain-dose ketamine infusion 💉 (especially useful given its ability to improve central opioid sensitivity and hyperalgesia). (37898187)
  • Central alpha-2 agonist (clonidine 💉 or dexmedetomidine 💉 ) has analgesic properties and synergizes well with ketamine (i.e., “ketadex”).
  • Methocarbamol 💉 (especially for musculoskeletal pain).
  • Pregabalin 💉 (selectively, for neuropathic pain).
  • NSAIDs 💉 may be considered in patients with adequate renal function.
  • Lidocaine infusion 💉 (if there is a niche for it, maybe it's here).
• (Additional discussion on multimodal analgesia: 📖)

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[#3/3] full opioid agonists for breakthrough pain

• Higher doses than usual will be required. (32827109)
• For patients on low to intermediate doses of buprenorphine (e.g., ~8-12 mg/day), full opioid agonists will have greater efficacy. When possible, it might be ideal to utilize agents with less euphoria potential (e.g., oral morphine) to avoid destabilizing the patient's OUD. (34775634)
• For patients on high doses of buprenorphine (e.g., >16 mg/day), high doses of fentanyl or hydromorphone may be required to compete with buprenorphine (given their higher affinity for mu  opioid receptors). (37898187)

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opioid use disorder & pregnancy

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• Ongoing opioid use disorder poses a massive risk to both mother and fetus. Consequently, effective treatment of OUD is essential in pregnancy.
• Safety of OUD medications in pregnancy:
  • Buprenorphine and methadone are both safe in pregnancy.
  • Previously, there were concerns that sublingual buprenorphine/naloxone wasn't safe in pregnancy. However, newer data have assuaged these fears and demonstrated that buprenorphine/naloxone is safe in pregnancy. (35007147, 32234267) 📄
• Buprenorphine is a preferred therapy for opioid use disorder throughout both pregnancy and breastfeeding. (30355476) The MOTHER trial showed that buprenorphine use in pregnancy causes less neonatal abstinence syndrome compared to methadone. (21142534) Buprenorphine should be continued during breastfeeding (drug transfer is minimal). 
  • Pregnancy causes an upregulation of CYP3A4, which will accelerate buprenorphine metabolism. Consequently, pregnant women may require an increased dose of buprenorphine dose and/or splitting the daily dose q12hr. (38100521)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• For patients with opioid use disorder, in addition to treating their acute problem, consider initiation of medication-assisted therapy. Simply patching up the acute problem and sending them home won't fix the underlying issue.
• For patients on chronic buprenorphine and acute pain, don't stop the buprenorphine. The key here is the addition of multimodal non-opioid therapies.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.