Opioid Addiction: Substitution Therapy

Opioid substitution therapy (OST), also called opioid agonist therapy (OAT) is used to prevent withdrawal symptoms in persons who discontinue long term use of analgesics that act on opioid receptors or as a treatment for people with opioid use disorder. OST includes conventional treatments such as methadone maintenance therapy and buprenorphine maintenance therapy.

Comorbid mental health disorders can interfere with the adherence to OST, and result in poorer outcomes of addiction treatment.

Characteristics of drugs used as OST⁽ⁱ⁾

Feature	Methadone	Buprenorphine
Dose required to prevent withdrawal symptoms according to degree of opioid dependency	Linear relationship (from 10-300 mg per day)	Linear relationship for persons with less opioid dependency only – ceiling effect (max daily dose 24 mg)
Interaction with ARVs	Methadone plasma concentrations are reduced if used together with: • NVP & EFV: ↓ 50% • LPV/r: ↓ 50% • No clinically significant alterations of methadone PK with other commonly used ART agents	Buprenorphine (B) and active metabolite norbuprenorphine (N) plasma concentrations are reduced if combined with NNRTIs and increased if combined with some PIs or INSTIs • EFV: ↓ up to 50% (B) and 70% (N) • ETV: ↓ 25% (B) • ATV/r: ↑ 50-100% (B&N) • DRV/r: ↑ 50% (N) • Caution: B reduces ATV; do not use without RTV or COBI boosting • EVG/c, ↑ 35-42% (B&N) (BIC, CAB, DOR, DTG, FTR, RAL, RPV & LPV/r do not affect B & N metabolism) • LEN may increase B however to an extent that does not warrant dose adjustment
	Caution: withdrawal symptoms if combined with ARV that decreases plasma concentration and risk of drug toxicity if such ARVs are interrupted – reverse if ARVs increase plasma concentration
Risk of overdose	Yes	See⁽ⁱⁱⁱ⁾
Causing QT prolongation on ECG	Yes (dose-response relationship)⁽ⁱⁱ⁾	No
Risk of obstipation	High	High
Type of administration	Tablet or liquid	Tablet applied sublingual
Risk of further impairment in persons with existing liver impairment	Yes	Yes

Feature

Methadone

Buprenorphine

Dose required to prevent withdrawal symptoms according to degree of opioid dependency

Linear relationship (from 10-300 mg per day)

Linear relationship for persons with less opioid dependency only – ceiling effect (max daily dose 24 mg)

Interaction with ARVs

Methadone plasma concentrations are reduced if used together with:
• NVP & EFV: ↓ 50%
• LPV/r: ↓ 50%
• No clinically significant alterations of methadone PK with other commonly used ART agents

Buprenorphine (B) and active metabolite norbuprenorphine (N) plasma concentrations are reduced if combined with NNRTIs and increased if combined with some PIs or INSTIs
• EFV: ↓ up to 50% (B) and 70% (N)
• ETV: ↓ 25% (B)
• ATV/r: ↑ 50-100% (B&N)
• DRV/r: ↑ 50% (N)
• Caution: B reduces ATV; do not use without RTV or COBI boosting
• EVG/c, ↑ 35-42% (B&N)
(BIC, CAB, DOR, DTG, FTR, RAL, RPV & LPV/r do not affect B & N metabolism)
• LEN may increase B however to an extent that does not warrant dose adjustment

Caution: withdrawal symptoms if combined with ARV that decreases plasma concentration and risk of drug toxicity if such ARVs are interrupted – reverse if ARVs increase plasma concentration

Risk of overdose

Yes

See⁽ⁱⁱⁱ⁾

Causing QT prolongation on ECG

Yes (dose-response relationship)⁽ⁱⁱ⁾

Risk of obstipation

High

Type of administration

Tablet or liquid

Tablet applied sublingual

Risk of further impairment in persons with existing liver impairment

Yes

See Drug-drug Interactions between Analgesics and ARVs
ECG recommended for daily methadone doses exceeding 50 mg; special caution with concomitant use of other drugs known to cause QT prolongation (e.g. certain ARVs (such as LPV/r, RPV, FTR), amiodarone, astemizole, azithromycin, clarithromycin, chloroquine, citalopram, domperidone, escitalopram, fluconazole and moxifloxacin)
Buprenorphine is commonly used as a fixed-dose combination with naloxone. Risk of overdose of buprenorphine may be reduced with the use of fixed dose combination with naloxone