Pharmacotherapy (Non-Opioid)

Report
Pharmacotherapy for Chronic Pain
Adapted from Penny Miller, BSc.(Pharm.), M.A.
www.pspbc.ca
Goal: Provide the physician with practical
information to support the medication management
of patients with chronic pain as one part of the
multimodal treatment to improve functioning, sleep
and reduce pain.
Learning Objectives:
At the end of this session, the physician will
demonstrate improved abilities to:
1. Identify select medications that have evidence for
the treatment of different types of chronic pain.
2. Discuss when and how to use appropriate
combinations of medications.
3. Outline the importance for slow upward titrations
and slow tapers off medications.
4. Discuss the contraindications and controversies
of medications used for chronic pain.
Medications cannot eliminate pain & are
merely a part of the overall treatment
Adjuvants
 An adjuvant is a medication that is not primarily
indicated for the treatment of pain, but which has
some evidence for chronic pain management
 Tricyclic antidepressants
 SNRIs (selective serotonin reuptake inhibitors)
 Anticonvulsants
 Topical agents
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Adjuvant Analgesics:
Anticonvulsants/Neuromodulators
For Chronic Neuropathic pain
Choosing Analgesics
The choice of a pharmacologic agent is based upon the following factors:
 Indication/ type and
intensity of pain
 Efficacy of agent for
the specific
indication (NNT)
 Safety and experience
of the agent (NNH)
 Renal and hepatic
function of patient
 Co-morbidities (e.g.
depression, cardiac
disease)
 Drug interactions
 Cost
 Dosing Schedule
 Dosage forms ( oral,
topical, parenteral,
etc.) & strengths
available
NNT= numbers needed to treat
NNH= numbers needed to harm
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Summary of Evidence – Cochrane Summaries
Drug
Indication
Clinical Considerations
Gabapentin
Postherpetic neuralgia NNT 8
Painful diabetic neuropathy
NNT 5.9
1200 mg daily x 8-12 weeks
Outcome: >50% pain
intensity 
Usually > 1 adverse effect
Postherpetic neuralgia NNT
3.9
Fibromyalgia NNT 11
300, 450, 600 mg daily for
benefits
Outcome: >50% pain
intensity 
Likely moderate benefit but
discontinue due to adverse
effects
CD007938 2014
Pregabalin
CD007076 2009
8
Summary of Evidence – Cochrane Summaries
Drug
Indication
Clinical Considerations
Carbamazepine No trial longer than 4
CD005451 2014
weeks for chronic
neuropathic pain or
fibromyalgia
Not enough good quality
studies to know the benefits
& harms  likely should not
be used
Lamotrigine
200 – 400 mg daily appears
to be effective but low
quality evidence, unable to
quantify; likely 10% will
have skin rash
CD006044 2013
Neuropathic pain &
fibromyalgia
9
What is the limitation of the evidence?

Gabapentin
› Issues of 40% of trials were unpublished

Pregabalin
›

Issue of unpublished trials
Carbamazepine no trial beyond 4 weeks
› Likely should not be recommended
 Lamotrigine 200 – 400 mg daily- There is no convincing
evidence this is effective in treating acute or chronic pain
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Adjuvant Analgesics/ Co-analgesics
Anticonvulsants/Neuromodulators: Gabapentin
Dose: start at 100 mg at bedtime and increase slowly (every
3 days) to 1800 – 3600 mg daily as tolerated (divided as
three times daily)
 Adjust dose in renal impairment (clearance is decreased)
 Absorption is inversely dependent on dosage:
› Gabapentin oral bioavailability:
80% with100 mg tid
27% with 1600 mg tid
 Analgesic effect seen at 2 to 3 weeks of therapeutic dose
11
Adjuvant Analgesics/ Co-analgesics
Anticonvulsants/Neuromodulators: Pregabalin
 Analgesic effect is seen within first week of therapeutic
dose
 Dose: start with 25 mg qhs and increase slowly (every 3 to
7 days) as tolerated to 150 mg daily or 150 mg bid (Max
600 mg daily)
 For all anticonvulsants, taper to elimination to avoid
seizures even with no history of convulsive disorder.
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Adverse Effects
Gabapentin
Pregabalin
Somnolence
21.4%
29.2%
Dizziness/ ataxia
28%
22.2%
Dry mouth
4.8%
9.1%
Peripheral Edema
8.3%
6.1%
Blurred Vision
5.9%
6.4%
↓ Concentration/attention
2.7%
5.4%
Clin Pharmacokinet 2010;49(10):661-669
Anesth Analg 2007:105:1805-15
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Anticonvulsant- Risk of suicidal thoughts and
behaviour
 0.43% on Anticonvulsants versus 0.22% on placebo
 Evident as early as 1 week after starting treatment
 Risk is highest in Epileptic cases
Neurology 2010; 75: 335-340
New Engl J Med 2010; 363: 542-451
CNS Drugs. 2009;23(4):281-92.
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Adjuvant Analgesics:
Antidepressants
For chronic pain
Summary of EvidenceCD005454 2007; CD008242 2012
Drug
Indication
Clinical Considerations
Amitriptyline
Painful diabetic
neuropathy/post-stroke pain
with fibromyalgia/postherpetic
neuralgia NNT 4.6
Potentially biased data – only 38%
benefited from therapy
Median duration 6 weeks
64% of participants with ≥ 1
adverse effect
A/E leading to withdrawal: NNH 28
Minor A/E: NNH 6
venlafaxine
Moderate pain relief NNT 3.1
A/E leading to withdrawal: NNH 16.2
Minor A/E: NNH 9.6
Antidepressants:
Diabetic neuropathy NNT 1.3
TCAs or venlafaxine Postherpetic neuralgia NNT 2.7
Duloxetine
2014
CD007115
Diabetic peripheral neuropathy
NNT 5
Fibromyalgia NNT 8
Studies were over 12 weeks – ie
short duration
60 mg daily
~12.6% participants dropped out
due to A/E
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Antidepressants/ TCAs
Adverse effects:
 Anticholinergic side effects (dry mouth: 30% amitriptyline/10%
nortriptyline), constipation, urinary retention, blurred vision, tachycardia,
cognitive impairment)
 Sedation (30% amitrip/2% nortrip), postural hypotension
 Cardiac arrhythmias ( especially in overdose)
 Weight gain
Precautions:
 Benign prostatic hypertrophy, closed angle glaucoma, CV disease
 Screening EKG for cardiac conduction abnormalities if > 40 yo
 Risk of suicide by overdose (> 750 mg or 15 - 20 mg per kg)
Dose: start with 10 mg amitriptyline at bedtime and titrate slowly
( analgesic response typically seen with 10 – 75 mg daily)
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Antidepressant (TCA) Monitoring
 Efficacy for improved sleep (immediate)
 Efficacy for improved pain control (1 -2 weeks)
Raskin et al Pain Med 2005
 Efficacy for improved mood (6 – 8 weeks)
 EKG baseline prior to initiation in patients over 40 years old
 Must taper off to avoid antidepressant discontinuation
syndrome
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Drug Interactions with TCAs
 TCA + Codeine – TCA block hepatic cytochrome 2D6
isoenzyme so inhibit conversion of codeine to morphine
(also, tramadol conversion to active metabolite)
 TCA +CNS depressants (alcohol, opioids)->sedation
 TCA + other anticholinergic – paralytic ileus
 TCA + SSRI or SNRI + Triptan = serotonin syndrome
 TCA + SSRI or SNRI + tramadol = serotonin syndrome
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Adjuvant analgesics/ Co-analgesics
Antidepressants - serotonin-norepinephrine reuptake
inhibitors (SNRI)
Mechanism of action: increase levels of norepinephrine ( and
serotonin) to stimulate the descending pain pathway
Duloxetine (Cymbalta ®)
 Start at 15 mg once daily (mix 30 mg capsule with apple sauce)
and titrate slowly up to 60 mg daily
 Dosage adjustment not necessary in renal dysfunction; caution
with hepatic insufficiency
Venlafaxine (Effexor ®)
 Start at 37.5 mg once daily and titrate slowly up to 150 mg (225
mg) daily
 Adverse effects: nausea, headaches, stimulation/sedation,
sweating, increased blood pressure
Minimal anticholinergic side effects
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Combination Therapy – Neuropathic Pain CD008943 2012
 Lots of different combinations
› difficult to evaluate & recommend one particular combination
 One sufficient evidence for gabapentin + opioid vs. gabapentin
alone
› N = 386, 2 studies
› Modest benefits, but combination was better
› A lot more adverse effects
 Tends to have overlapping adverse effects of CNS sedation
› High dropout rates in studies – limit utility of such
combinations
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Topical agents
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What is the evidence for topical agents?
 Capsaicin low dose 0.075% gel: Systematic review with usage over 6
to 8 weeks
› NNT 6.6 (95% CI 4.1-1.7) for NP
Cochrane Database
Syst Rev 2012;9:CD010111
› NNT 8.1 for osteoarthritis (pain reduction of 33-55% vs 20 -27%
placebo)
Rheumatology (Oxford)
2011;50(5):911-20
“it unlikely that low-concentration topical capsaicin has any meaningful
use in clinical practice”
Cochrane Database syst. Rev. 2012 Sep 12;9:CD010111
 NSAIDs : Meta-analysis of RCTs (diclofenac)
› NNT 4.6 (95% CI 3.8 -5.9) for knee osteoarthritis
›
BMC Musculoskelet Disord 2004:5:28; J Rheumatol 2006;33(9):1841-4
› Contact dermatitis risk
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Treatment Principles





First consider non-drug measures.
Is a medication ESSENTIAL? (i.e. clear diagnosis)
Is the treatment GOAL/ outcome clear?
Initiate one drug at a time. Keep it simple.
Select pharmacologic classes with efficacy
demonstrated (ideally) in multiple RCTs
 Be aware that response will vary between patients
 Start with very low doses and titrate slowly
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Treatment Principles…
 When introducing a new treatment, consider
overlap with old treatments to avoid deterioration
in pain control.
 If the new medication is well tolerated, then
continue to titrate to effective or acceptable pain
relief (30% to 50% reduction)
 Consider adding a second agent with a different
mechanism of action if the first agent is providing
partial relief yet pain remains ≥ 4/10
 If the medication is ineffective, then slowly taper
off the medication
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Treatment Principles…
 Consider side effects, drug interactions, cost and
abuse potential
 Be aware of comorbidities such as depression,
anxiety and insomnia
 Design a future plan to slowly taper off most
medications for chronic pain
 Educate patients about their medications
 Regularly update the medication lists of patients
(OTC, herbal, Rx)
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Summary
 The complex task of pain management should be approached with
a logical foundation:
› A detailed history and physical
› Any appropriate testing that can facilitate diagnosis and
treatment
› Establishment of realistic and desired common goals of further
treatment and/or evaluation
› Formulation of a treatment plan that may include only a rational,
evidence-based approach in the use and selection of
medications
› Flexibility in modification of treatment based on periodic reassessment
› Referral to a pain specialist when appropriate
› A trusting and caring relationship is an important
imperative
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