1. Pharmacotherapy for Chronic Pain
Adapted from Penny Miller, BSc.(Pharm.), M.A.
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2. 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:
Identify select medications that have evidence for the treatment of different types of chronic pain.
Discuss when and how to use appropriate combinations of medications.
Outline the importance for slow upward titrations and slow tapers off medications.
Discuss the contraindications and controversies of medications used for chronic pain.

3. Medications cannot eliminate pain & are merely a part of the overall treatment
Multimodal Therapeutic strategies for chronic pain and Associated disability

5. 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 24

6. Adjuvant Analgesics: Anticonvulsants/Neuromodulators
For Chronic Neuropathic pain

7. Indication/ type and intensity of 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
NNT= numbers needed to treat
NNH= numbers needed to harm
Co-morbidities (e.g. depression, cardiac disease)
Drug interactions
Cost
Dosing Schedule
Dosage forms ( oral, topical, parenteral, etc.) & strengths available

8. Summary of Evidence – Cochrane Summaries
Drug
Indication
Clinical Considerations
Gabapentin CD
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
Pregabalin CD
Postherpetic neuralgia NNT 3.9
Fibromyalgia NNT 11
300, 450, 600 mg daily for benefits
Likely moderate benefit but discontinue due to adverse effects
Although the NNT does not appear to be very high and seems very favourable, keep in mind the outcome is >50% pain intensity reduction. This suggests there is likely some moderate benefit and may not necessarily be experienced by all patients.
Consider using functional goals to evaluate and monitor therapy.

9. Summary of Evidence – Cochrane Summaries
Drug
Indication
Clinical Considerations
Carbamazepine CD
No trial longer than 4 weeks for chronic neuropathic pain or fibromyalgia
Not enough good quality studies to know the benefits & harms  likely should not be used
Lamotrigine CD
Neuropathic pain & fibromyalgia
200 – 400 mg daily appears to be effective but low quality evidence, unable to quantify; likely 10% will have skin rash

10. 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
Painful Diabetic neuropathy (PDN); IMMPACT definition of pain applied for moderate and substantial benefit in Gabapentin trials

11. 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
is a branched- chain amino acid (similar to leucine) which affects oral bioavailability
Clin Pharmacokinet 2010;49(10):

12. 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.
Pain Res Manage 2007:12(1):13-21 Guidelines CPS; Pain Res Manage 2006;11(1):11-38 Chronic Pain review – Lynch Lyrica 300 mg starting dose caused significant analgesia within one to 3 days.

13. 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): Anesth Analg 2007:105:
Sedation is #1 reason to DC (4%)
For Gabapentin: Cochrane Review: Cochrane Database Syst Rev Mar 16;3:CD
66% have at least one adverse event; 12% withdrawal because of an adverse event; 4% serious adverse events which were no more common than with placebo.

14. 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:
New Engl J Med 2010; 363:
CNS Drugs. 2009;23(4):
(FDA 2008) Meta- analysis of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs (antiepileptic drugs) showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomized to placebo.
Andersohn F, Schade R, Willich SN. et al .Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behaviour. Neurology 2010; 75:
5 Arana A, Wentworth CE, Ayuso-Mateos JL. Arellano FM. Suicide-related events in patients treated with antiepileptic drugs. New Engl J Med 2010; 363:
CNS Drugs. 2009;23(4):
Suicidality in people taking antiepileptic drugs: What is the evidence?

15. Adjuvant Analgesics: Antidepressants
For chronic pain

16. 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: TCAs or venlafaxine
Diabetic neuropathy NNT 1.3
Postherpetic neuralgia NNT 2.7
Duloxetine CD
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
Third row refers to any evidence for TCAs or venlafaxine

17. 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 mg per kg)
Dose: start with 10 mg amitriptyline at bedtime and titrate slowly
( analgesic response typically seen with 10 – 75 mg daily)
Amit Nortrip dry mouth 30% 10% sedation 30% 2%
The most important ECG feature of toxicity is prolongation of the QRS interval, which indicates a high risk of ventricular tachycardia. In very severe poisoning the ECG may be bizarre. Rarely, prolongation of the PR interval or heart block may occur. QT interval prolongation and torsade de pointes has also been reported.

18. 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
Antidepressant discontinuation syndrome: (FINISH) Flu-like symptoms, insomnia, Nausea, sensory disturbances (electric shocks), Hyperarousal ( anxiety, confusion, hypomania)

19. 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
Celecoxib also : Journal citation: Proceedings of the National Academy of Sciences, advance publication online Dec. 1,

20. 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
Pain Res Manage 2007:12(1):13-21 Guidelines CPS; Pain Res Manage 2006;11(1):11-38 Chronic Pain review – Lynch

21. 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

22. Topical agents

23. 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 ) for NP Cochrane Database Syst Rev 2012;9:CD010111
NNT 8.1 for osteoarthritis (pain reduction of 33-55% vs % 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 Sep 12;9:CD010111
NSAIDs : Meta-analysis of RCTs (diclofenac)
NNT 4.6 (95% CI ) for knee osteoarthritis
BMC Musculoskelet Disord 2004:5:28; J Rheumatol 2006;33(9):1841-4
Contact dermatitis risk

24. 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

25. 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

26. 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)

27. 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 re- assessment
Referral to a pain specialist when appropriate
A trusting and caring relationship is an important imperative