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!