Pharmacological management of Opioid Use Disorder

1. PHARMACOLOGICAL
MANAGEMENT OF OPIOID
USE DISORDER
SOUMEN KARMAKAR

2. Opioid Receptors:
▪ 3 major types- μ1, μ2 ; δ1, δ2 ;κ1 , κ2, κ3 . (Minor types – NOP & ζ )
▪ Analgesia (μ,δ,κ) ; Physical dependence (μ,δ) ; Euphoria (μ)
▪ μ-receptor inVTA expressed in GABAergic inhibitory interneurons
and inhibit them, leading to disinhibition of dopamine neurons &
reward pathway.
(Ref: Katzung Pharmacology, 13th ed)

3. Physiological Effects of Opioids (CNS)
▪ Analgesia
▪ Euphoria/ dysphoria
▪ Sedation
▪ Respiratory depression
▪ Suppression of cough reflex
▪ Miosis
▪ Truncal rigidity
▪ Nausea & vomiting
▪ Temperature (↑ed/↓ed)
▪ Sleep architecture
▪ Coma and death

4. Effects of Opioids (Other organs)
▪ Cardiovascular: bradycardia, orthostatic hypotension
▪ Gastrointestinal system: motility ↓, tone ↑, constipation
▪ Biliary tract: sphincter of Oddi constriction, colic
▪ Urinary: retention
▪ Endocrine: ↓ FSH/LH, ↓ testosterone, ↑ prolactin level, amenorrhoea,
↓ libido & energy
▪ Skin: itching, sweating, rash including urticaria

5. Harmful Effects of Opioid Use:
▪ Respiratory Depression, Cerebral Anoxia, Delirium, Coma, Death
▪ ↑ prevalence of HIV, Hep-C
▪ Tuberculosis
▪ ↑ Mortality: 2-4% per annum, 13 times higher than peers. (Overdose,
Violence, suicide, smoking, alcohol, other substances use)
▪ Reduction in quality of life
▪ Economic burden
(Ref: WHO guidelines on opioid dependence, 2009)

6. Goals of Treatment:
▪ Reducing or ceasing opioid use
▪ Preventing future harms associated with opioid use
▪ Improving quality of life and well-being.

7. Modalities of Treatment:
▪ Opioid overdose:
 Antagonist – Naloxone
▪ Opioid Withdrawal:
 Agonist – Methadone
 Partial Agonist – Buprenorphine
 Symptomatic – α2 agonist clonidine
▪ Prevent Relapse:
 Antagonist - Naltrexone

8. OPIOID OVERDOSE:
▪ Respiratory depression & unconsciousness/ coma.
▪ Airway, Breathing, Circulation
▪ Naloxone IV 0.2-0.4mg stat. If no response after 2-3 minutes (respiratory
rate/ mydriasis), then repeat IV 1-2mg.
▪ 1-2mg IV initial to patients in apnea/cardiorespiratory arrest.
▪ Maintenance (infusion or repeated injection) for longer acting opioids (as
t1/2 60-90 min)
▪ Higher dose needed for buprenorphine, methadone, phentanyl overdose.
▪ AIM: Respiration rate 12/min or more, oxygenation 92% or more.

9. OPIOID OVERDOSE (cont.)
▪ May be given SC or IM if IV not feasible.
▪ Naloxone tx may precipitate withdrawal.
▪ Agitation
▪ Pulmonary edema (rapid withdrawal).
▪ No effect with 10 mg Naloxone, alternate diagnosis to be considered
(e.g. Benzodiazepines, alcohol)
(Ref: Kaplan & Sadock, CTP 10th ed)

10. OPIOID WITHDRAWAL (DETOXIFICATION):
▪ The primary goals of detoxification are
▪ (1) safe removal of the opioid and the physiological dependence, and
prevent life-threatening complications that might happen if opioid
withdrawal is left untreated
▪ (2) to stabilize the patient’s physical and psychological health to
allow them to initiate medication assisted relapse-prevention
treatment

11. Detoxification Strategies
▪ Symptomatic treatment only with nonopioid medication
▪ Agonist assisted detoxification
▪ Antagonist-assisted detoxification with symptomatic treatment.
▪ The main difference is that in agonist-assisted detoxification
withdrawal symptoms tend to be more severe toward the later part of the
treatment and may continue after treatment completion while in
symptomatic treatment only and antagonist-assisted detoxification,
withdrawal symptoms are more severe early in the treatment and are
usually minimal later in the treatment
(Ref: Kaplan & Sadock, CTP 10th ed)

12. WFSBP 2011 guideline recommendation:

13. USFDA APPROVED AGENTS:
▪ Currently 4 agents approved forTx of Opioid Dependence.
 Methadone (approved 1972)
 Buprenorphine (approved 2002)
 Oral Naltrexone (approved 1984)
 Injectable, long acting Naltrexone (approved 2010)
(Ref: Kaplan & Sadock, CTP 10th ed)

14. METHADONE:
▪ Synthetic full opioid agonist, l & r form, racemic mixture
▪ Good oral bioavailability, used in liquid form for OST (tablets and
injections also available)
▪ Variable half life (12-150 hours), Peak effect 1-2hours
▪ Metabolized by CYP3A4
▪ Less tolerance than Morphine, heroin.
▪ S/E: constipation, respiratory depression, excessive sweating,
decreased libido, QTc prolongation at higher dosages.
(Ref: Kaplan & Sadock, CTP 10th ed)

15. BUPRENORPHINE:
▪ High affinity partial μ agonist with Ceiling effect, κ antagonist.
▪ May precipitate withdrawal if used early during detoxification.
▪ Poor oral bioavailability, used S/L.
▪ T1/2 24-48 hours, peak effect 2-4 hours
▪ Metabolized by CYP3A4
▪ S/E: nausea, headache, GI upset, sweating, somnolence, ↓ libido,
constipation, (lesser chance of QTc ↑)
(Ref: Kaplan & Sadock, CTP 10th ed)

16. BUPRENORPHINE:NALOXONE (4:1)
▪ Suboxone
▪ Naloxone has poor oral S/L bioavailability. Effective IV
▪ If Suboxone used by Injection route, naloxone blocks agonistic effect
of Buprenorphine, even may precipitate withdrawal.
(Ref: Kaplan & Sadock, CTP 10th ed)

17. NALTREXONE:
▪ High affinity & long acting μ antagonist
▪ Reduce craving, even in presence of cues.
▪ Patient to be fully detoxified before starting (7-10 days opioid free)
▪ Oral, long acting injection(monthly) and implants(3-6months)
▪ Contraindicated in patients taking any opioids (OST)
▪ Not metabolized by hepatic CYP450 enzymes.
▪ Monitor for Liver disease.
▪ S/E: nausea, diarrhea, anxiety, insomnia
(Ref: Kaplan & Sadock, CTP 10th ed)

18. CLONIDINE:
▪ α2 adrenergic agonist
▪ Symptomatic relief for autonomic features of
withdrawal(sweating, tremors, restlessness, rhinorrhea)
▪ Does not relief bone/muscle pain, insomnia
▪ S/E postural hypotension.
▪ Lesser S/E with Lofexidine
▪ Guanfacine also tried
(Ref: Kaplan & Sadock, CTP 10th ed)

19. RECOMMENDATIONS (OST):
▪ Inpatient vs OutpatientTx: No added advantage of one over another.
Inpatient: for severe withdrawal, concurrent medical/psychiatric
comorbidities, poor social support.
Outpatient: Cost effective, generally the preferred setting.
▪ Choice ofTx: Maintenance agonist therapy preferred over withdrawal
strategies.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

20. Methadone vs Buprenorphine
▪ “In studies to date, methadone at standard doses has been more effective
in retaining people in treatment and reducing heroin use than
buprenorphine at standard doses; also, methadone is cheaper.”
▪ “Although buprenorphine treatment might be expected to be safer than
methadone treatment, this has not been confirmed by research.”
▪ “Currently, high-quality methadone provision should be considered the
optimal treatment, with buprenorphine reserved for second-line therapy
for patients in whom methadone is unwanted, inappropriate or ineffective.
Patients who inject buprenorphine should be prescribed methadone in
preference to buprenorphine.”
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

21. INITIAL DOSE OF METHADONE:
▪ For patients on prescribed opioids, the total daily dose should be converted to an
equivalent methadone dose given once daily.
▪ The first two weeks of methadone treatment is a high-risk period for overdose,
because it can be difficult to assess with certainty the level of neuroadaptation.
▪ Recommendation: “During methadone induction, the initial daily dose should
depend on the level of neuroadaptation; it should generally not be more than 20
mg, and certainly not more than 30mg.”
▪ Once it has been established that the initial dose is well tolerated, the methadone
dose should be gradually increased until the patient is comfortable and not using
heroin or other illicit opioids.The rate of increase should be individually assessed,
and should generally not be greater than 10 mg every few days.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

22. Equivalence dose of different opioids:
(Ref: Kaplan & Sadock, CTP 10th ed)

23. Methadone Dose Conversion:
(Ref: Kaplan & Sadock, CTP 10th ed)

24. INITIAL DOSE OF BUPRENORPHINE:
▪ The risk of overdose during buprenorphine induction is low.
▪ In patients with high neuroadaptation to opioids buprenorphine may precipitate
withdrawal symptoms initially, and such patients may benefit from lower initial
doses (2 mg).
▪ In addition, patients should wait until they are experiencing mild opioid withdrawal
before taking the first dose of buprenorphine to reduce the risk of withdrawal
symptoms precipitated by buprenorphine.
▪ Patients with moderate levels of neuroadaptation will generally tolerate initial
doses of 4–8 mg a day.
▪ Once it has been established that the initial dose is well tolerated, the
buprenorphine dose can be increased fairly rapidly to a dose that provides stable
effects for 24 hours and is clinically effective.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

25. MAINTENANCE DOSE:
▪ On average, methadone maintenance doses should be in the range of 60–
120 mg per day.
▪ Buprenorphine: doses should be at least 8 mg per day. If patients are
continuing to use illicit opioids, consideration should be given to increasing
the dose by 4–8 mg, to a limit of 32 mg daily.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

26. SUPERVISION:
▪ Methadone and buprenorphine doses should be directly supervised
in the early phase of treatment.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

27. DOSE TAPERING:
▪ METHADONE:
Inpatient: after 24-48 hours of dose stabilization, reduction @10-
20% or 5mg per day. Detoxification completed within 1 week.
Outpatient: at least 4 weeks dose stabilization, then slow reduction
(preferred, e.g. 3% per week). Detoxification completed within 1-2
months.
 BUPRENORPHINE:
24 hours of dose stabilization, reduction @2mg per day, 1mg per day
reduction on last 2 days. Detoxification completed within 5-7 days.
(Ref: Kaplan & Sadock, CTP 10th ed)

28. DURATION OF TREATMENT:
▪ There is little research on the optimal duration of opioid agonist treatment
▪ Opioid agonist treatment should be seen as open ended, and should be
continued as long as clinically indicated
▪ Factors predicting successful termination of opioid agonist maintenance
treatment are not well described, but are likely to include employment or
other meaningful activity, abstinence from opioid and other drug use while
taking opioid agonists, and changes in the psychosocial environment after
starting opioid agonist treatment
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

29. RELAPSE PREVENTION:
▪ For opioid-dependent patients not commencing opioid agonist
maintenance treatment, antagonist pharmacotherapy using Naltrexone
should be considered following the completion of opioid withdrawal.
▪ Retention in treatment is generally likely to be lower than opioid agonist
maintenance therapy; nevertheless, in those patients who have withdrawn
from opioids and are motivated to cease opioid use completely, relapse
prevention efforts with naltrexone are likely to be superior to those without
naltrexone.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

30. ANTAGONIST THERAPY:
▪ Commenced after withdrawal is completed. ( 2-3 days after low dose
of maintenance agonists).
▪ 50 mg tablets daily, or thrice weekly regime with 100 mg on Mondays
&Wednesdays, and 150 mg on Fridays
▪ Monthly injection has better relapse prevention results.
(Ref: Kaplan & Sadock, CTP 10th ed)

31. WITHDRAWAL ASSESSMENT: Severity
▪ OOWS: Objective OpioidWithdrawal Scale
▪ SOWS: Subjective OpiateWithdrawal Scale
▪ COWS: Clinical Opiate Withdrawal Scale

32. WITHDRAWAL: Clinical Features
Sweating*
Lacrimation (ExcessiveTear
Formation)*
Yawning*
Feeling Hot And Cold*
Anorexia And Abdominal
Cramps*
Nausea
Vomiting And Diarrhoea*
Tremor
Insomnia And Restlessness*
Generalized Aches And Pains*
Tachycardia
Hypertension*
Piloerection (Gooseflesh)
Dilated Pupils
Increased Bowel Sounds
*SOWS

33. Degree of Tolerance to effects of Opioids
▪ High: analgesia, euphoria, sedation, respiratory depression, cough
suppression, nausea & vomiting, mental clouding
▪ Moderate: Bradycardia
▪ Minimal or Low: Miosis, constipation, convulsion

34. RECOMMENDATION FOR Mx OF WITHDRAWAL:
▪ For the management of opioid withdrawal, tapered doses of opioid
agonists should generally be used, although alpha-2 adrenergic
agonists may also be used.
▪ Buprenorphine is suitable for once-daily administration; it leads to
less severe withdrawal and higher rates of completion than alpha-2
agonists.
▪ Methadone is cheaper than buprenorphine and carries no risk of
precipitated withdrawal; it is suitable for use in pregnancy.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

35. RECOMMEDNDATION(cont.):
▪ Buprenorphine and methadone are both recommended in the
management of opioid withdrawal. As a partial agonist with slow receptor
dissociation, buprenorphine has the best pharmacological profile for use in
withdrawal, reducing the risk of rebound withdrawal when opioids are
ceased. While buprenorphine is probably slightly more effective, it is more
expensive
▪ Alpha-2 agonists can lead to shorter duration of withdrawal symptoms and
shorter time to commencement of naltrexone.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

36. RECOMMENDATION(cont.):
▪ The duration of the dose taper should be at least 3 days, with a taper over 5
days for buprenorphine and 10 days for methadone resulting in acceptable
withdrawal symptoms during treatment and minimal rebound withdrawal
symptoms on cessation of the opioid agonist.
▪ Lofexidine should be used in preference to clonidine, particularly in
outpatient settings, because it has less adverse effects.
▪ Accelerated withdrawal strategies not preferred.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

37. SPECIAL POPULATIONS:
▪ HIV: ART to be delayed until patient stabilized on maintenance
therapy.
▪ TB: ATD should be started concomitantly.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

38. PREGNANCY:
▪ Opioid not teratogenic. Risk of miscarriage, PROM, premature
delivery, low birth weight, preeclampsia
▪ Neonatal Abstinence Syndrome
▪ Antagonist not used in 1st & 3rd trimester. (spontaneous
abortion/premature birth)
▪ Opioid agonist maintenance treatment should be used for the
treatment of opioid dependence in pregnancy.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

39. PREGNANCY(cont.)
▪ Methadone maintenance should be used in pregnancy in preference
to buprenorphine maintenance for the treatment of opioid
dependence; although there is less evidence about the safety of
buprenorphine, it might also be offered.
▪ Methadone dose may need to be increased in 2nd trimester.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

40. POLYSUBSTANCE USE:
▪ InpatientTx needed for concomitant Alcohol, Benzodiazepines,
Stimulants, Cannabis use
▪ In Outpatient setting, ceasing benzodiazepines should be tried
before opioids.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

41. ACUTE PAIN IN OPIOID DEPENDANTS:
▪ For Mild to Moderate: NSAIDS
▪ Not on Opioid Maintenance: Methadone
▪ On Methadone: Injectable NSAIDS, Patient controlled analgesia,
higher dosage of Opioid analgesics due to tolerance.
▪ On Buprenorphine: ↑ dose, add Tramadol, Fentanyl (high affinity),
Ketamine infusion; May stop Buprenorphine temporarily
▪ On Naltrexone: Regional anesthesia, continuous sedation,
Ketamine infusion. For elective surgery- Omit 72hours prior,
restart 3-7 days after.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

42. CHRONIC PAIN IN OPIOID DEPENDANTS:
▪ Thorough & comprehensive assessment.
▪ Not on maintenance: Agonist therapy
▪ On maintenance: Supervised dosing, opioid rotation
▪ May try cessation of maintenance therapy if Opioid induces
Hyperalgesia suspected.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)

43. ALTERNATIVE STRATEGIES FOR OPIOID
DEPENDENCE MANAGEMENT:
▪ The limited evidence is inadequate to support any recommendations on heroin
maintenance.
▪ The limited evidence is inadequate to support any recommendations on slow or
sustained-release oral morphine.
▪ Although still registered in the United States, Levo-alpha-acetylmethadol (LAAM) has
been withdrawn from the market by the manufacturer, due to the risk of life-
threatening cardiac arrhythmias.
▪ The limited evidence is inadequate to support any recommendations on a
buprenorphine–naloxone combination. However, the combination is likely to have
similar efficacy to buprenorphine alone.
▪ The limited evidence is inadequate to support any recommendations on slow-release
naltrexone implants and injections.
(Ref:WHO Opioid DependenceTreatment Guidelines, 2009)

44. PSYCHOSOCIAL SUPPORT:
▪ Psychosocial support should be offered routinely in association with
pharmacological treatment for opioid dependence.
(Ref: WHO Opioid DependenceTreatment Guidelines, 2009)
▪ Hypnotherapy, psychotherapy, acceptance and commitment
therapy, interpersonal psychotherapy, supportive–expressive
psychotherapy, counselling, cognitive behavioural therapy (CBT),
contingency management(CM), dialectic behaviour therapy and
comprehensive validation therapy.
▪ CM & CBT particularly useful.
(Ref: Kaplan & Sadock, CTP 10th ed)

45. Unanswered Question:
▪ How long Relapse prevention therapy with Naltrexone to be
continued?

46. Thank You