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Opioid and Benzodiazepine Reduction Strategies Launette Rieb MD, MSc, CCFP, FCFP, dip. ABAM Clinical Associate Professor,, Department of Family Practice, University of British Columbia Disclosures No commercial interests Objectives Clarify the pharmacology of opioid and benzodiazepine use and withdrawal Increase skill at detoxifying patients from opioids and benzodiazepines using the following techniques: Opioid withdrawal symptom management Opioid tapering Opioid substitution Papaver Somniferum Opioids Bind to opioid receptors Relieving pain (psychological and physical) dopamine (DA) in pleasure centres (ventral tegmental area nucleus accumbens) noradrenalin (NOR) in the fight or flight centres (locus coeruleus and amygdala), calming Affects brainstem (OD from respiratory depr.) Can produce dysphoria, sedation, impaired judgment, constipation, weight gain, erectile dysfunction (from decreased testosterone) Opioids – Higher Doses Can increase the risk of… Unintentional OD Substance misuse and addiction Tolerance Via NMDA pathway activation Opioid receptor desensitization, internalization Opioid Induced Hyperalgesia Via NMDA pathway activation Suppression or even cell death among descending pain control neurons Dose-related risk of opioid overdose Risk of adverse event 10 9 8 7 6 Dunn 2010 Risk Ratio 5 Bohnert 2011 Gomes 2011 4 Zedler 2014 3 2 1 0 <20 mg/day 20-49 mg/day 50-99 mg/day Dose in mg MED >=100 mg/day Courtesy Gary Franklin Prescription Opioids “Watchful Dose” in morphine equivalent daily dose (MEDD) 120 mg Washington 120 mg Worksafe BC 200 mg Canadian Opioid Use Guidelines only 20-30% with LOT –Yet we chase the fantasy of perfect analgesic control Analgesia Withdrawal can be very painful (especially at sites of old injury) drive further use Opioid Withdrawal Withdrawal is not life threatening Unless patient has a history of seizures, is dehydrated, suicidal or pregnant Warn patients of OD risk post detox Opioid Withdrawal DSM-5…3+ within minutes to days of stopping: Dysphoria N or V muscle aches lacrimation or rhinorrhea diarrhea yawning fever insomnia Pupillary dilitation, piloerection or sweating When to Suggest Opioid Taper? Patient on opioids without significant improvement in pain and function Safety sensitive position Spread of pain in the absence of disease progression allodynia and hyperalgesia Active substance abuse/dependence where harm reduction not viable Patient requests to come off Where to start? First make a diagnosis Use? Substance Use Disorder? Pseudoaddiction? Is there physiologic dependence? Is a withdrawal syndrome present? How severe? Life threatening? What is the patient’s circumstance? Support setting? Mental and physical health? Opioid w/d Management Protocol for short acting opioids like morphine, oxycodone or heroin For use when you cannot or will not prescribe opioids, eg street opioid use A caregiver should accompany patient to appointments, agree to attend & dispense then you can give 1 week’s worth of meds Daily dispensed from the pharmacy if reliability of the caregiver an issue Opioid w/d Management Environment: Reliable support person, safe, no caffeine, mild food, min exercise, avoid hot bath/shower/sauna Clonidine 0.1mg qid x4d, tid x1d, bid x1d, hs x1d all prn Test dose 0.1mg, BP pre & 1-4h post in the office can be done (eg. For young women) BP >90/60, if lower - give clonidine 0.05 mg tabs Decreases temperature dys-regulation (hot/cold flashes) and NOR (insomnia & anxiety) Warn pts of postural hypotension Opioid w/d Management, Diazepam* 5 mg qidx4d, tidx1d, bidx1d Decreases anxiety, insomnia If benzo tolerant: 10mg dosing – close f/u Trazodone* 50 mg 1-2 tabs hs for insomnia Loperamide 2 mg after loose stool, 8/d max Dimenhydrinate 25mg 1-2 tid N+V Ibuprofen 400 mg q 6-8h for pain Acetaminophen 500mg q6h for pain * Nb quetiapine 25 mg tid and 100 hs can be used instead of diazapam and trazadone Opioid w/d Management, Try to start on a Monday (not Friday) Try to start medicines after 1d off heroin/morph Try to see or call in frequently Adjust medications according to symptoms If patient relapses, review symptoms (ask what was the worst part of the w/d) and try again – adjusting meds. Make a backup plan in the beginning – eg. if home detox fails x2 then residential detox or methadone (often more effective than detox) Opioid Tapering Options Options to withdrawal from legally obtained Rx opiates for pain (not addiction): 1. 2. 3. Taper with current short acting medication formulation Convert short acting into long acting of the same opioid, then taper Substitute another type of opioid then taper. AKA opioid rotation. Opioid Tapering – Short Acting Sometimes easiest to simply taper what the patient is currently using – even if short acting E.g. Oxycodone/APAP 16-20/d, taken 6 tid +/- 2/d If it is a dual agent first switch to eliminate the ASA or acetaminophen (bloodwork?) E.g. Oxycodone 5 mg 18/d Next spread out the daily dose evenly based on the ½ life of the medication E.g. Oxycodone 5 mg 5/4/4/5 spread q6h Opioid Tapering – short Next taper the medication – depending on the patient’s symptoms the drop can be ever 4 -14 days, always dropping nighttime dose last Oxycodone 5 mg 4/4/4/5 spread q6h Oxycodone 5 mg 4/4/4/4 spread q6h Oxycodone 5 mg 4/3/4/4 spread q6h Oxycodone 5 mg 4/3/3/4 spread q6h Oxycodone 5 mg 3/3/3/4 spread q6h Oxycodone 5 mg 3/3/3/3 spread q6h Continue this pattern until 0/0/0/1, then off Opioid Tapering – short If patient using a combination of short and long acting – conventional wisdom is to taper short first, but since often this is what patients “feel” and are attached to you can taper it last Oxycodone ER 80 mg q12 h plus oxycodone 10mg 1-2 prn 4/d max Taper Oxycodone ER first by 10 mg every 4-14 days dropping morning dose, then evening dose Hold the oxycodone short 10 mg at q6h until off the Oxycodone ER then taper by 5 mg as per previous schedule leaving the hs to be last off Opioid Tapering - convert Conventional wisdom is to convert short acting opioids to long acting then taper Sometimes short is needed to add back in at the end due to dose strength Convert to long acting (same drug less 25% - 50%, rest is given as short acting PRN at 1st) If changing opiates beware of conversion Lack of cross tolerance with some opiates Once on just long acting: Taper ~5-10% per wk If the patient has lots of social support can try tapering 10% q 4d Opioid Tapering – Convert Pt taking hydromorphone (short) 200 mg/d 1st conversion: Hydromorphone (long) 75 mg q12 h plus hydromorphone (short) 4mg 1q4h prn – warn about driving, sedation 2nd week: see if prn doses needed – if so add in as long acting, e.g. 100 mg q12h 3rd week on…taper 5-10%, typically faster at first and slower at the end of the taper Taper until on lowest dose strength long 3q12h Then re-introduce short to complete weekly taper, e.g. hydromorphone (short) 2mg q8h; 1mg q6h; 1mg q8h; 1mg am and hs;1mg hs;off Risk of Addiction (or Relapse) Those at highest risk: Active SUD Past Hx of SUD Family Hx of SUD Active psychiatric illness Past Hx of chronic pains requiring opioids++ Tight contracts, follow-up, and collateral In Patients at High Risk for SUD Prescribe only for well-defined somatic or neuropathic pain conditions Start with lower doses and titrate in small dose increments Monitor closely for signs of aberrant drug related behaviors – send for assessment and treatment if needed Alcohol and benzodiazepine use is incompatible with opioid prescribing Opiate Addiction Abstinence Counseling Medications Agonist Peer Support Methadone Residential Treatment Buprenorphine Antagonist Naltrexone Opioid Substitution Therapy Methadone and buprenorphine/naloxone (bup/nx) can be used for pts with an opioid use disorders and pain Dose once daily to eliminate withdrawal and block other opioids – may be sufficient Methadone or bup/nx used for pain +/- SUD can be dosed q6-8h Bup/nx currently off label for pain alone though can argue physiologic dependence, tolerance Methadone and bup/nx are used for detox METHADONE Morphine to Methadone Oral morphine to methadone 24 hour total oral morphine conversion ratio <30 mg 2:1 31-99 mg 4:1 100-299 mg 8:1 300-499 mg 12:1 500-999 mg 15:1 >1000 mg 20:1 Managing Cancer Pain in Skeel ed. Handbook of Cancer Chemotherapy. 6th ed., Phil, Lippincott, 2003, p 663 Results 646/4183 sustained successful tapers = 13% Younger, males, better tx adherence, lower mean max weekly doses Longer tapers better 12-52 weeks vs <12 weeks OR 3.58 >52 weeks vs <12 weeks OR 6.68 More gradual, stepped tapering schedule 25-50% vs <25% of taper weeks OR 1.61 Patterns of Methadone Dose Tapering (Most successful checked) Modified from Nosyk et al, Addiction 2012; 107(9):1621-9. Precipitated Withdrawal Buprenorphine/naloxone – bup/nx – only a “partial agonist” in vitro, but is really a full agonist at the mu opioid receptor in vivo slightly better than morphine for receptor saturation and pain relief Has higher AFFINITY for the mu opioid receptor than anything but fentanyl thus will kick off other opioids and put the person into withdrawal until the buprenorphine is high enough to relieve withdrawal kappa receptor antagonist, may help mood Bup/nx and Pain Daitch D et al. Pain Medicine. 2014 Retrospective chart review of patients on over 200 MEDD converted to Suboxone - pain scores dropped 51% on average, 8/10 to 4/10 Average 4 point drop! Daitch D et al. Pain Medicine. 2014 Naltrexone – opioid antagonist Post detox use naltrexone 50mg/d po for those with OUD can block 0.5+ gm of heroin IV or equivalent Start 1-2 wks after last short acting opioid (3-4 wks post methadone) ¼ pill day 1; ½ pill day 2; 1 pill day 3 onwards Witnessed ingestion is best Contraindicated cirrhosis, OD risk high once d/c Use for first 6-12 months of sobriety from OUD Analgesia with non-opioids or get consult Naloxone Take Home Kits Nasal or injectable naloxone kits given to people prescribed opioids for pain or addiction Train Pt and others living with them Can save lives in OD situations Sometimes Pt uses it on a friend Find out what is available/allowable in your area Evidence for Use Only real indication is for alcohol withdrawal Poor evidence for Generalized Anxiety Disorder, Obsessive Compulsive Disorder, Post Traumatic Stress Disorder, Major Depressive Disorder (including augmentation), or schizophrenia May be indicated for short term therapy in insomnia or acute anxiety short term (i.e. panic disorder) but note that needs CBT alongside and can create refractory anxiety – not a monotherapy indication Benzo - Adverse Cognitive Effects Acute (sedation, impairment of learning, slowing, anterograde amnesia) Chronic (visuospatial impairment, reduced cognitive functioning) Increased Alzheimer’s OR 1.4 (Billioti BMJ Aug 2014) Psychomotor Effects Driving ability Falls, accidents and injuries Mortality – HR 3.6 – 5.3 (Kripke BMJ 2012) Contraindicated with other sedatives e.g. ORT like methadone, bup/nx, alcohol, muscle relaxations – studies show increased mortality Benzodiazepines Binds to GABA-BNZ receptors and allow chloride to enter cell thus hyperpolarizing it Withdrawal criteria same as for alcohol Both use and w/d can be life threatening Residential detox if both ETOH & benzo (polypharmacy) W/d may last weeks, occasionally months High dose, long duration, short acting benzos all risks for difficult or prolonged w/d Meta-analysis on tapering protocols inconclusive of the best rate – best to engage patients, some promise with substitute therapies Benzodiazepine – withdrawal Discuss Anxiety symptoms – irritability, insomnia, panic attacks, poor concentration Neurological symptoms – ringing in the ears, blurred vision, distorted perception, depersonalization Let with patients what to expect: them know if they get shaky to stop taper Tremor is clearest sign pre-seizure Need to reassess, perhaps take extra dose Benzodiazepines – w/d Abrupt Risk seizure, psychosis or delirium Consider residential tx if abrupt cessation >80mg Office cessation of > = diazepam 50 mg/d mngt: Convert to long acting benzo Smooth blood level decreases symptoms Diazepam can be used if young and healthy Clonazepam good alternative for w/d from alprazolam or triazolam Lorazepam if cirrhosis or elderly Benzodiazepines - Tapering Give 75% diazepam equiv. - divided q8h Plus breakthrough prn doses of the rest Reassess in 1 week or less, establish dose Taper diazepam by 2–5 mg q1-2 wks (5%) No regular breakthroughs If short term use – faster, if long term – slower Can initially drop faster if dose over 50 mg/d Trazodone 50 hs or propranolol 10-20 tid may help decrease prolonged w/d symptoms Benzo tapering – another approach Alternatively you can substitute in the diazepam slowly while decreasing the other benzodiazepine Since there may not be perfect cross tolerance some find this more comfortable Some find lorazepam more anxiolytic and diazepam more sedating Diazepam allows the dose to go lower before discontinuing. Benzodiazepine equivalences Adapted from The Ashton Manual and The Clinical Handbook of Psychotropic Drugs (19th Ed.) Benzodiazepine Comparative Dose (mg) Alprazolam 0.25-0.5 Clonazepam 0.25 Lorazepam 0.5-1 Diazepam 5 Oxazepam 10-15 Temazepam 10 Ashton Protocol Dr. Heather Ashton from the UK Protocol for very slow benzo conversion and taper of diazepam (can apply the same principle to opioid tapering if needed) Use for highly sensitive patients Those on for many years Elderly Failed conventional tapering Withdrawal from lorazepam1mg TID Adapted with permission from slides of R. Chadha Stage Morning Afternoon Evening Stage 1 (1/52) Loraz. 1 mg Loraz. 1 mg Loraz. 0.5 mg 30 mg Diaz. 5 mg Stage 2 (1/52) Loraz. 0.5 mg Loraz. 1 mg Diaz. 5 mg Loraz. 0.5 mg 30 mg Diaz. 5 mg Stage 3 (1/52) Loraz. 0.5 mg Loraz. 0.5 mg Loraz. 0.5 mg 30 mg Diaz. 5 mg Diaz. 5 mg Diaz. 5 mg Stage 4 (1/52) Loraz. 0.5 mg Loraz. 0.5 mg (Stop Loraz.) Diaz. 5 mg Diaz. 5 mg Diaz. 10 mg 30 mg Stage 5 (1/52) (Stop Loraz.) Diaz. 10 mg 30 mg Loraz. 0.5 mg Diaz. 10 mg Diaz. 5 mg Diaz. Equiv. Withdrawal from lorazepam Stage Morning Afternoon Evening Diaz. Equiv. Stage 6 (1/52) Diaz. 10 mg Stop loraz. Diaz. 10mg Diaz. 10 mg Stage 7 (1-2/52) Diaz. 10 mg Diaz. 7 mg Diaz. 10 mg 27 mg Stage 8 (1-2/52) Diaz. 7 mg Diaz. 7 mg Diaz. 10mg Stage 9 (1-2/52) Diaz. 7 mg Diaz. 4 mg Diaz. 10 mg 21 mg Stage 10 (1-2/52) Diaz. 5 mg Diaz. 4mg Diaz. 10 mg 19 mg Stage 11 (1-2/52) Diaz. 5 mg Diaz. 2 mg Diaz. 10mg 30 mg 24 mg 17 mg Withdrawal from lorazepam Stage Morning Afternoon Evening Stage 12 (1-2/52) Diaz. 3 mg Diaz. 2 mg Diaz. 10 mg 15 mg Stage 13 (1-2/52) Diaz. 3 mg (Stop Diaz.) Diaz. 10mg Stage 14 (1-2/52) Diaz. 2 mg ----------------- Diaz. 10 mg 12 mg Stage 15 (1-2/52) (Stop Diaz.) ----------------- Diaz. 10 mg 10 mg Stage 16----------------- ----------------- Reduce by Completion 1 mg every 2/52 Diaz. Equiv. 13 mg 9 mg – 0 mg Benzo withdrawal management Some other medications have been tried in withdrawal for symptomatic therapy: SSRI for depressive symptoms TCAs, melatonin, trazodone for insomnia Propranolol for severe palpitations, gastric upset ?Muscle relaxants No real good evidence for this but is clinically relevant in engaging patients in withdrawal Novel studies being done with pregabalin, gabapentin, and other anti-epileptics Pharmacological assisted benzodiazepine discontinuation 1st line: Phenobarbital Acts as a weak agonist at GABA receptor Long t1/2, minimal withdrawal, generally well-tolerated and effective Dosing: 30 – 60 mg bid – qid 2nd line: Gabapentin 100 – 300 mg tid Pregabalin 50 – 75 mg qhs – tid (Dr Mark Weiner, Ann Arbor, Mich., Pain Recovery Solutions) Effects of pregabalin on subjective sleep disturbance during withdrawal from long term benzodiazepine use N = 282 Pregabalin dose 315 mg/day (mean) Decrease in insomnia scores (week 12) Pregabalin 55.8 +/- 18.9 Placebo 25.1 +/- 18.0 Improvements in anxiety symptoms (Rubio G et al, Eur Addict, Jun 2011) Residential Detox When to consider residential detox? If unsuccessful with out-patient detox If out of control with meds If other SUDs suspected Patient requests to get w/d over with faster Significant psychiatric or physical symptoms symptoms emerge Mr. D. 47 year old married at home father, degree is psychology, no family history of SUD Age 19: L4-5 discectomy for prolapse Post-op give Tylenol #3 He mixed these with ETOH to get high years later – recurrent disc – surgery Initially successful then increasing low back pain over the next year 10 Mr. D, con’t GP managed Tried different medications, low dose at 1st Hydromorphone short acting up to 80 mg/d Would run out early, would crush and smoke Fluoxetine 60 mg/d Lorazepam 4 mg/d Pain still unmanageable on above regime Referred on Mr. D., con’t Multidisciplinary hospital based pain clinic Medications altered, various medications combined Opioids were increased over time to the level below: Fentanyl Patch 150 mcg/h q2 d (prescribed q3d) +/- fentanyl solution 100 mcg/2ml vile 3-5/d Fentanyl film 600 mcg bid = 1200 mcg/d Tramadol (24h) 50 mg ii bid = 6 tabs/d = 300 mg/d Methadone tablets 60 mg bid = 120 mg/d Hydromorphone - short acting 80 mg/d (snorting) Morphine equivalent dose = 1,830+ mg/d Mr. D., con’t Other medications Fluoxetine 80 mg/d (adverse rxn - duloxetine) Diazepam 2.5 mg bid (+still using lorazepam) Decongestant with pseudoefedrine 2 tabs/d Caffeine pills and energy drinks He still felt pain, otherwise felt “Great!” Function: ran triathlons, others see sedation Total cost to wife’s insurance = $3,000/wk Mr. D., con’t Voluntary admission to a medically supervised residential treatment facility: education, 12 step, group, 1:1, CBT, etc. Methadone and fluoxetine same dose at 1st Stopped tramadol on admission Stopped all fentanyl after 2 d taper Added quetiapine 25 mg q6h No withdrawal seen Mr. D., con’t Tapered the methadone over 3 weeks to 5 mg tid Dose held until in withdrawal Switched to buprenorphine patch 10 mcg initially – not quite enough Then over to sublingual bup/nx titrated to 6 mg/d where he has been maintained successfully Mr. D., followup Follow-up 12 months post admission to recovery Meds Bup/nx 6 mg/d Fluoxetine 60 mg/d and tapering Quetiapine 125 mg/d and tapering Has attended 12 step daily, has a sponsor No relapses or slips, despite divorcing No more pain issues GAF 95/100 Mr. D., Reflections Primary pain disorder or substance use disorder? Opioid induced hyperalgesia? How can the opioids besides methadone be stopped abruptly without withdrawal? How can bup/nx and 12 step combined control both the pain and addiction issues? Opioids - Highlights Patients with physiologic dependence on opioids and/or benzodiazepines who need to come down or off can be assisted by a variety of approaches: Symptom management Replacement and tapering Agonist therapy Antagonist therapy (naltrexone) Education and non-pharmacologic options Key References Chou, R. et al. The Effectiveness and Risks of Long-Term Opioid Therapy for Chronic Pain: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(4):276286. doi:10.7326/M14-2559 Fishman, S. Responsible opioid prescribing, 2nd edition. 2014. Waterford Life Sciences, Washington, DC Furlan A. et al. Opioids for chronic non-cancer pain: A new Canadian guideline. www.cmaj.ca and http://nationalpaincentre.mcmaster.ca/opioid/ Ashton H. The Ashton Manual.Information for Physicians, Patients, Taper schedules. Website: benzo.org.uk Kahan M., Wilson L. Managing Alcohol, tobacco and other drug problems: A pocket guide for physicians and nurses. CAMH Centre for Addiction and Mental Health, 2002 Thank you!
