Opioid and Benzodiazepine Reduction Strategies

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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

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Disclosures

• No commercial interests

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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

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Papaver Somniferum
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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)

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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

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Dose-related risk of opioid overdose
Courtesy Gary Franklin
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Prescription Opioids

• Watchful Dose
• in morphine equivalent daily dose (MEDD)
• 120 mg Washington
• 120 mg Worksafe BC
• 200 mg Canadian Opioid Use Guidelines
• Analgesia only 20-30 with LOT Yet we chase the
  fantasy of perfect analgesic control
• Withdrawal can be very painful (especially at
  sites of old injury) drive further use

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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

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Opioid Withdrawal

• DSM-53 within minutes to days of stopping
• Dysphoria
• N or V
• muscle aches
• lacrimation or rhinorrhea
• diarrhea
• yawning
• fever
• insomnia
• Pupillary dilitation, piloerection or sweating

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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

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Where to start?

• First make a diagnosis
• Use? Substance Use Disorder? Pseudo-addiction?
• Is there physiologic dependence?
• Is a withdrawal syndrome present?
• How severe? Life threatening?
• What is the patients circumstance?
• Support setting? Mental and physical health?

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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 weeks worth of meds
• Daily dispensed from the pharmacy if reliability
  of the caregiver an issue

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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 gt90/60, if lower - give clonidine 0.05 mg tabs
• Decreases temperature dys-regulation (hot/cold
  flashes) and NOR (insomnia anxiety)
• Warn pts of postural hypotension

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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 NV
• 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

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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)

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Opioid Tapering Options

• Options to withdrawal from legally obtained Rx
  opiates for pain (not addiction)
• 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.

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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

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Opioid Tapering short

• Next taper the medication depending on the
  patients 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

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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

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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

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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 ontaper 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 hs1mg hsoff

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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

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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

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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

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METHADONE
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Morphine to Methadone
24 hour total oral morphine Oral morphine to methadone conversion ratio
lt30 mg 21
31-99 mg 41
100-299 mg 81
300-499 mg 121
500-999 mg 151
gt1000 mg 201
Managing Cancer Pain in Skeel ed. Handbook of
Cancer Chemotherapy. 6th ed., Phil, Lippincott,
2003, p 663
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Results

• 646/4183 sustained successful tapers 13
• Younger, males, better tx adherence, lower mean
  max weekly doses
• Longer tapers better
• 12-52 weeks vs lt12 weeks OR 3.58
• gt52 weeks vs lt12 weeks OR 6.68
• More gradual, stepped tapering schedule
• 25-50 vs lt25 of taper weeks OR 1.61

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Patterns of Methadone Dose Tapering (Most
successful checked)
?
?
Modified from Nosyk et al, Addiction 2012
107(9)1621-9.
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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

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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
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Daitch D et al. Pain Medicine. 2014
Average 4 point drop!
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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

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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

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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

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Benzo - Adverse

• Cognitive Effects
• Acute (sedation, impairment of learning, slowing,
  anterograde amnesia)
• Chronic (visuospatial impairment, reduced
  cognitive functioning)
• Increased Alzheimers 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

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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

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Benzodiazepine withdrawal

• Discuss with patients what to expect
• Anxiety symptoms irritability, insomnia, panic
  attacks, poor concentration
• Neurological symptoms ringing in the ears,
  blurred vision, distorted perception,
  depersonalization
• Let them know if they get shaky to stop taper
• Tremor is clearest sign pre-seizure
• Need to reassess, perhaps take extra dose

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Benzodiazepines w/d

• Abrupt cessation of gt diazepam 50 mg/d
• Risk seizure, psychosis or delirium
• Consider residential tx if abrupt cessation gt80mg
• Office 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

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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 25 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

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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.

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Benzodiazepine equivalencesAdapted 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
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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

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Withdrawal from lorazepam1mg TID Adapted with
permission from slides of R. Chadha
Stage Morning Afternoon Evening Diaz. Equiv.
Stage 1 (1/52) Loraz. 1 mg Loraz. 1 mg Loraz. 0.5 mg Diaz. 5 mg 30 mg
Stage 2 (1/52) Loraz. 0.5 mg Diaz. 5 mg Loraz. 1 mg Loraz. 0.5 mg Diaz. 5 mg 30 mg
Stage 3 (1/52) Loraz. 0.5 mg Diaz. 5 mg Loraz. 0.5 mg Diaz. 5 mg Loraz. 0.5 mg Diaz. 5 mg 30 mg
Stage 4 (1/52) Loraz. 0.5 mg Diaz. 5 mg Loraz. 0.5 mg Diaz. 5 mg (Stop Loraz.) Diaz. 10 mg 30 mg
Stage 5 (1/52) (Stop Loraz.) Diaz. 10 mg Loraz. 0.5 mg Diaz. 5 mg Diaz. 10 mg 30 mg
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Withdrawal from lorazepam
Stage Morning Afternoon Evening Diaz. Equiv.
Stage 6 (1/52) Diaz. 10 mg Stop loraz. Diaz. 10 mg Diaz. 10mg 30 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 24 mg
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 17 mg
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Withdrawal from lorazepam
Stage Morning Afternoon Evening Diaz. Equiv.
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 13 mg
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-Completion ----------------- ----------------- Reduce by 1 mg every 2/52 9 mg 0 mg ?
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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

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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)

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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)

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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

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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
• 10 years later recurrent disc surgery
• Initially successful then increasing low back
  pain over the next year

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Mr. D, cont

• 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

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Mr. D., cont

• 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

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Mr. D., cont

• 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 wifes insurance 3,000/wk

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Mr. D., cont

• Voluntary admission to a medically supervised
  residential treatment facility education, 12
  step, group, 11, 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

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Mr. D., cont

• 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

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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

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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?

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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

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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. 2015162(4)276-286.
  doi10.7326/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

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• Thank you!