Event 2: Neuromodulating Agents

Modulation of Pain by Neuromodulating Agents

Treatment of Neuropathic Pain

The current state of neuropathic pain treatment is not satisfactory
It is estimated that over 2/3 of patients do not obtain sufficient pain relief
Existing treatments do not fully target suspected pain-generators

Reference

Pain 2011;152:2204-5

Neuropathic Pain is Difficult to Treat

Reference

Adapted from Wong, 2008; Chong 2007, and other sources.

Neuropathic Pain Guidelines

Guidelines generally concur that TCAs and gabapentin are first line agents: e.g. post-herpetic neuralgia, diabetic neuropathy, central neuropathic pain.
Selective noradrenergic reuptake inhibitors (SNRIs) are generally recommended as first or second-line agents
Opioids mostly 3rd line agents, after other agents have been tried.
Local anesthetics may be used in topical preparations, e.g. patch or cream

Reference

*Canadian, European and IASP NeuPSIG

Guidelines: Diabetic Peripheral Neuropathy

Pregabalin should be offered for the treatment of painful diabetic neuropathy (PDN) (Level A)
Gabapentin and sodium valproate should be considered for the treatment of PDN (Level B)
Amitriptyline, venlafaxine, and duloxetine should be considered for the treatment of PDN (Level B). Data are insufficient to recommend one of these agents over the others.
Venlafaxine may be added to gabapentin for a better response (Level C)
Morphine, tramadol, oxycodone, dextromethorphan should be considered

Reference

Neurology 2011;76:1–1

Gabapentinoids

Gabapentin

Originally developed as an anti-convulsant
Inhibits calcium influx through the a2d calcium channel sub-unit
Among the first-line drugs for neuropathic pain
Good safety profile; minimal drug-drug interactions
May start at 300 mg/day or 100 mg/day for elderly
QHS dosing during first week may minimize complaints of dizziness
Wide dosing range: 600 – 3600 mg daily, divided doses
renal dosing adjustment may be necessary
Half-life means 3X/daily dosing is optimal

Pregabalin

Inhibits calcium influx through the a2d calcium channel sub-unit
Among the first-line drugs for neuropathic pain
FDA approved for painful diabetic neuropathy and PHN
May have quicker onset of action compared to gabapentin
May be associated with dizziness, sleepiness, ankle edema, weight gain
Schedule V controlled substance: mild euphoria reported in some patients during clinical trials
Twice daily dosing, more convenient for some patients
Begin as 50mg tid or 75mg bid
May require renal dosing

Pain-Active Anti-Depressants

Evidence is best for tricyclics (TCAs)
Selected SSRI/SNRIs antidepressants may have more favorable side effect profile
Proven efficacy for various forms of neuropathic pain
Treatment effects begin after a delay that ranges from 1 week (desipramine), to two weeks or longer.
Tricyclics generally require lower doses for efficacy against pain, compared with the treatment of depression. By contrast, newer SNRIs require treatment at standard antidepressant doses to be effective against pain.

Tricyclic Antidepressants

TCAs

Long track record of efficacy against neuropathic pain
Adverse effects range from:
- Life threatening at higher doses (QT prolongation)
- Dangerous: glaucoma, urinary retention
- Bothersome: dry mouth leading to accelerated dental decay
- Potentially useful: sedation with amitriptyline can be helpful to patients with delayed sleep onset due to night-time neuropathic pain
Drug interactions (P450 2D6) need to be checked
Not generally subject to abuse
Due to cardiac profile, screening EKG recommended for those with cardiac history or over 50 prior to initiation of therapy.

Reference

Pain 2011;152:2206-2210

TCAs

Amitriptyline
- Most sedating TCA (profound sedation, helpful for night-pain)
- Severe dry mouth may lead to accelerated tooth loss, requires a plan for dental care
- Highly effective against neuropathic pain,
- May be effective at doses as low as 10 mg QHS
- may be safely used for long periods of time
Nortriptyline
- Prodrug, metabolized to amitriptyline
- Favorable side effect profile although constipation, urinary retention and sexual dysfunction may occur
Desipramine
- Least sedating, causes tachycardia in some patients

Duloxetine: Pain-active SNRI

FDA approved for painful diabetic neuropathy, chronic musculoskeletal pain and fibromyalgia as well as major depressive disorder and generalized anxiety disorder
Side effects can include – nausea, somnolence, urinary hesitancy, seizures, withdrawal syndrome, serotonin syndrome, suicidal ideation, headache
CYP1A2 inducers decrease effect
Dose: can start at 30 mg/day and increase to 60 mg/day, doses can range as high as 120 mg/day under appropriate supervision
Compared with TCAs, patients are somewhat less likely to attain a clinically significant benefit, the NNT is 5.3-6

Venlafaxine: Pain-active SNRI

Demonstrated to be effective for the treatment of neuropathic pain, moderate effect size
FDA approved for the treatment of major depressive disorder
Side effects include headache, hypertension, nausea, constipation, seizures, somnolence
Serotonin syndrome may be prominent. In addition medication cessation syndrome may occur as well, gradual tapering on and off is recommended.
Treatment can start at 37.5mg bid or 37.5mg daily
Max dose: 225mg daily
Extended release formulations may be better tolerated
NNT 3.1-5.2

Reference

Pain 2007;132:237-251, 2011;152:2206-2210

Opioid Analgesics

Opioids have been shown to be effective against neuropathic pain in RCTs (PHN, PDN)
Guidelines generally recommend opioids as third line agents however prescriber discretion is permissible, e.g. for those patients unable to tolerate, or allergic to first and/or second line agents
Opioids have established side effect profiles that may exacerbate underlying syndromic problems, e.g. constipation in those with peripheral neuropathy
Opioids have a complimentary mechanism of action and can be used in conjunction with other neuromodulating agents in appropriate clinical settings

Other Neuromodulating Agents

Tramadol

Synthetic, centrally-acting analgesic: reuptake inhibition of NE and serotonin, in addition, a major metabolite is an opioid agonist
Published trials in PDN and polyneuropathy
Adverse effects include nausea, diarrhea, constipation, dizziness, somnolence, orthostatic hypotension, seizures, serotonin syndrome
Often well-tolerated and quite effective
Dose ranges from: 50-400mg/day, typical starting dose: 50 mg twice daily

Lidocaine

Lidocaine Patch 5%
- Shown to be effective in patients with PHN (RCTs)
- Minimal blood levels of lidocaine
- Patch must be worn 12 hours on, 12 hours off
- Mild skin reactions can occur
- Patches may be cut and tiled, with oversight
Lidocaine cream
- Lidocaine and other neuromodulating agents can be compounded into creams and topical preparations
- A reputable compounding pharmacist should be contacted directly by the prescriber.

Clonidine

α-2 Adrenergic agonist
nonspecific analgesic effects at the dorsal horn
FDA approved for cancer pain via epidural administration

NMDA-Receptor Antagonists

Ketamine: widely used in children, also used in management of polytrauma, dissociative anesthetic; generally administered in combination with midazolam I.V.
Dextromethorphan: most widely used as an antitussive; occasionally used as an adjunct to other pain therapies. Effects demonstrate rapid tachyphylaxis, generally not appropriate to pain management in a primary care setting.

Summary

There are multiple agents that are effective against neuropathic pain, however no single agent has been proven completely effective and therapy must be individualized.
Selected anticonvulsants are effective against neuropathic pain, the gabapentinoids have been highlighted here as well tolerated and generally recommended for the treatment of neuropathic pain
Selected antidepressants are effective against neuropathic pain, these include several of the tricyclic antidepressants and some of the SNRIs.
Other agents are known to be effective against neuropathic pain in selected patients and therapeutic trials can be undertaken by experienced practitioners.