Partial Agonists & Half-Truths: The use of buprenorphine – naloxone in the treatment of chronic pain Canadian Society of Addiction Medicine XXIV Annual Meeting and Scientific Conference Ottawa, Ontario October 18, 2014 Andrew J Smith, MDCM Staff Physician, Neurologist, Pain and Addiction Medicine Centre for Addiction and Mental Health, Toronto
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Partial Agonists & Half-Truths:
The use of buprenorphine – naloxone in the treatment of chronic pain
Canadian Society of Addiction Medicine
XXIV Annual Meeting and Scientific Conference
Ottawa, Ontario
October 18, 2014
Andrew J Smith, MDCM
Staff Physician, Neurologist, Pain and Addiction Medicine
Centre for Addiction and Mental Health, Toronto
+ Faculty/Presenter Disclosure
Faculty: Andrew J Smith, MDCM
Relationship with commercial interests
None
+ Learning Objectives
By the end of the session, participants will
be able to:
1. List at least three clinical scenarios in
which sublingual buprenorphine-naloxone
could be used in patients with chronic pain
2. Describe the role of buprenorphine-
naloxone in managing opioid misuse and
addiction in patients with chronic non-
cancer pain as outlined in the Canadian
(NOUGG) guidelines.
+ Discussion of Off-Label/Investigational
Use of Commercial Products
This activity contains information about
clinical and experimental uses of drugs
that are not currently approved by Health
Canada and/or other national regulatory
agencies in Canada.
Participant are encouraged to consult the
Health Canada approved product labelling
for any drug mentioned in this program
before use.
+ Question
What percentage of North Americans are
currently experiencing pain which has
gone on for more than 6 months?
1. 2%
2. 5%
3. 10%
4. 25%
+ The Burden of Chronic Pain
Prevalence of chronic pain in the adult population may be 30% (Moulin et al 2001)
18% of Canadian adults suffer from moderate to severe chronic pain daily or most days of the week (Nanos Survey 2007-2008)
Chronic pain is associated with an increase in the use of health services (Tarride, Gordon et al 2005)
Massive economic burden: $635 billion per annum in US (US Institute of Medicine, 2011) 6x that of depression
Mostly due to decreased productivity, not absenteeism
Interventional approaches: nerve stimulation or block
Acupuncture
Botox
ETC…
+ Case JB: Wasser Clinic Diagnoses
•IBD – untreated
•Chronic abdominal pain
•Visceral nociceptive pain
•Chronic neuropathic component
•Poorly managed on high-dose opioids – unstable
opioid regimen Meq (720 mg/day)
•Complicated by high tolerance and likely opioid-
induced hyperalgesia
•? SI joint/ankylosing spondylitis
•Risk: high – FH+, h/o mood comorbidity, h/o trauma,
LD, ? UDT result
+ Case JB: Wasser Recommendations
•GI – consideration of DMARD Rx, etc •Imaging of spine, SI joints, HLA B27 •UDT: GCMS today •d/c all hydromorphone •Outpatient morphine taper: Kadian (morphine) 400mg qDay + Statex 10mg up to 4/day; weekly dispensing •Taper by 10% (40mg) every 2 weeks until at 200mg/day, then reassess •Opiate contract •UDTs on regular basis •Consider psych eval
A Canadian Approach to Opioids
NOUGG – with representation from all MRAs in Canada
Treatment of pain
Evidence-based
Collaborative
Autonomy
Clinician and Patient Input
Practice Improvement
Implementation
Practice Resources
+ Overview of NOUGG Guidelines
1. Deciding to initiate opioid therapy
1. Conducting an opioid trial
1. Monitoring long-term opioid
therapy
1. Opioids in specific populations
1. Managing opioid misuse and
addiction in CNCP patients
NOUGG Guidelines
CLUSTER 1: Deciding to Initiate
“Before initiating opioid therapy, consider the evidence related to effectiveness in patients with chronic non-cancer pain.”
Opioid Efficacy – NOUGG Recommendation # 4
+ Opioid Efficacy – NOUGG Review
The updated systematic review of opioids for CNCP included 62 randomized trials
Opioids were compared to placebos in 47 randomized trials
The effect size for improvement in pain was medium (0.58 95% confidence interval [CI]: 0.48 to 0.67, extracted from 47 RCTs)
For functional outcomes, the effect size was small (0.34 95% CI: 0.25 to 0.43, extracted from 31 RCTs)
+ GCMS
POS fentanyl, norfentanyl
Hydromorphone
Alprazolam
D-methamphetamine, amphetamine
+ Pay no attention to that man behind the curtain….
+ Urgent Follow-Up
UDT results reviewed
Additional history obtained
Accessing opioids from street – fentanyl
smoking
Started using methamphetamine to counteract
sedation associated with opioid use
Benzos to counteract amphetamines
+ Reformulation of Dx and Plan
Substance use disorder – opioid, amphetamines,
benzos
IBD – untreated
Chronic abdominal pain
? SI joint/ankylosing spondylitis
Refer to Medical Withdrawal Service at CAMH
Discontinue all opioids – rotate onto Suboxone for
pain/opioid use disorder
Follow-up at CAMH
NOUGG Guidelines
CLUSTER 5: Managing Opioid Misuse and
Addiction
For patients with chronic non-cancer pain who are addicted
to opioids, three treatment options should be considered:
1. Methadone or buprenorphine treatment (Grade A)
2. Structured opioid therapy (Grade B), or
3. Abstinence-based treatment (Grade C)
Consultation or shared care, where available, can assist in
selecting and implementing the best treatment option
(Grade C)
Why Bup/Nal vs Methadone?
Ontario Drug Benefit – LU Code 437 For the treatment of opioid dependence in patients who have failed,
have significant intolerance, have a contraindication to, or who are at high risk for toxicity with methadone
use of benzodiazepines
alcohol abuse or dependence
elderly
patients who are dependent on codeine or abuse opioids on a less than daily basis
on medications that interfere with methadone metabolism
at high risk for prolonged QT interval.
NOTE: Physicians should complete an accredited course on opioid addiction and buprenorphine treatment before prescribing Suboxone.
Buprenorphine
Partial opioid agonist
Ceiling effect
Buprenorphine - Pharmacology
Lipophilic ideal for TD preparations (vs 40% S/L
bioavailabilty)
Slow-onset and long-offset
Transmucosal route – even longer… t1/2 19-27 hr
High affinity to u-opioid receptor…competing with other
opioids that bind there
Has slow rate of dissociation from u receptor
prolonged duration of action compared with other
opioids
Agonist at delta -OR and OLR receptors
Buprenorphine - Pharmacology
ORL-1
In brain- anti-analgesic effect in animals; dampens
dopaminergic reward system
At spinal level –anti-nocicipetion
Slows onset of opioid tolerance
Agonism…may be effective for treatment of neuropathic pain
KAPPA-OR ANTAGONIST…blocks dysphoric and
psychotomimetic effects of K agonism
Inhibition of voltage-gated Na channels
Buprenorphine - Pharmacology
Metabolized though hepatic CYP3A4 (primary), CYP2C8,
Glucuronide-conjugated byproducts eliminated in feces by biliary
excretion 4-6d after admin
Minimal urinary excretion
All analgesic EXCEPT norbup-3-gluc
Norbup and norbup-3-gluc cause RESP DEPRESSION,
SEDATION…
NOT so with bup and bup-3-glucuronide
NB other meds that compete for metabolic parthways..eg
benzos
Hyperalgesia: “Opioid-induced Pain”
Tolerance
resistance to opioid
desensitization down-regulation
Dose
Hyperalgesia
hyperesthesia +/- allodynia
anatomically distinct
qualitatively different
long- and short-term therapy
NMDA
Dynorphin
μ-opioidRc cAMP
Dose
+ Possible Antihyperalgesic Action of
Buprenorphine
Pergolizzi J et al. Pain Practice. 2010
Partial Agonist?
Partial agonist = inability to produce the same level of effect
as some reference full-agonist drug in a given situation
What do we mean?
Intrinsic activity biological stimulus imparted by drug to a receptor
Efficacy level of drug-induced effect for a given outcome
(manifested at a particular endpoint) eg…ANALGESIA, RESP
DEPRESSION
BUP has low in vitro intrinsic activity as measured in several
receptor binding assays PARTIAL AGONIST MONIKER
Does BUP produce less effect compared to a reference drug?
Raffa et al. J. Clin Pharm and Therapeutics. 2014
Partial Agonist ?
Morphine also produces <100% effect
Bup acts at multiple receptors total analgesic effect results from activity at several receptors
Bup displays > 98% noci efficacy in animal models
PET scans of human brains show that full analgesia achieved with bup doses that occupy < 100% of opioid receptors
Raffa et al. J. Clin Pharm and Therapeutics. 2014
Buprenorphine – Full Agonist –Clinical Evidence
Inclusion: human, within-study comparison of same pain type and with drugs commonly considered to be full agonists, quantification of pain severity or pain relief; comparison using the same pain scales
EXCLUSION: non-human; use as part of a combination; use in opioid addiction (eg Suboxone)
24 clinical trials identified + 1 case report and 1 dose-response curve
Based on complete or comparable pain relief, buprenorphine had full clinical analgesic efficacy in 25/26 of these studies