Neuropathic Pain
Pharmacological Therapy
Treatment of neuropathic pain includes the use of opioids and adjuvant analgesics.
Traditional teaching that neuropathic pain is unresponsive to opioids cannot be upheld. The majority of children with life limiting conditions experience a significant improvement of their neuropathic pain following the application of opioids. (2)
Opiods:
Methadone (see other opiates section)
Tramadol:
- Synthetic centrally acting analgesic with both opioid and non-opioid properties.(4, 5)
- Stimulates neuronal serotonin release and inhibits the presynaptic re-uptake of both noradrenaline (norepinephrine) and serotonin.
- This weak mu receptor antagonist has a ceiling effect and a very good safety profile regarding respiratory depression. (2)
- Dose generally used:
- Tramadol PO 1-2 mg/dose q 4 h. Max 8 mg /kg/day.
- Patients > 50 kg : max 400 mg/day
Ketamine:
- Anesthetic agent that can produce profound analgesia and amnesia without depressing the respiratory and cardiovascular systems.
- Ketamine (in pediatric practice) in low subanesthetic doses is effective for the treatment of postoperative pain, non surgical acute nociceptive pain and neuropathic pain, both alone or in combination with opioids.(2)
- Activation of NMDA receptors secondary to pain stimuli increases spinal neuron reception of pain due to hyper excitability of dorsal root neurons. Ketamine’s effectiveness in neuropathic pain is due to its high potency as an NMDA receptor channel blocker.
- Other actions that may contribute to its analgesic effect are interactions with noradrenergic and serotoninergic re-uptake inhibition and mu-, delta-, and kappa-opioid like effect.
- Generally ketamine is used in addition to morphine or alternative strong opioids when further opioid increments have been ineffective or precluded by unacceptable undesirable effects.
- Ketamine is extensively metabolized by the liver’s cytocrome P450 system. Due to its high hepatic extraction and the minimal renal excretion of intact ketamine, doses do not need to be altered in moderate renal or hepatic failure.
- Oral ketamine is more potent than SC ketamine because first pass metabolism converts ketamine to the major active metabolite norketamine. The dose of ketamine orally is approximately half of that given subcutaneously.
- The contents of a vial can be given orally. The bitter taste can be disguised by masking the dose with pure fruit juice or a soft drink immediately before administration.
- Side effects: Some ketamine secondary effects are
- hypertension
- tachycardia
- excessive salivation/ lacrimation
- nystagmus.
- psychotomimetic phenomena (vivid dreams, hallucinations and alterations in body image) are less frequently seen at sub-anesthetic analgesic doses given PO or via SC and generally can be controlled with benzodiazepines.
- Absolute contraindications included raised intracranial pressure and uncontrolled epilepsy.
Table: Doses of ketamine generally used in children - Subanesthetic dose (low dose) for analgesia and adjuvant analgesia for managing neuropathic pain: (2)
Patient weight |
Dosage |
Less than 50 kg |
IV/SC 0.04 – 0.15 mg/kg/hr. Titrated to effect. Max: 0.3 - 0.6 mg/kg/hr. |
PO 0.2 - 0.4 mg/kg/dose Tid-Qid and PRN. |
|
More than 50 kg |
IV/SC 2 - 5 mg/hr. Titrated to effect in 2 - 4 mg/hr escalations every 24 hrs. |
PO 10 - 25 mg/dose Tid-Qid and PRN. Increase dose in steps of 10 - 25 mg up 50 mg Qid. |
Tricyclic Antidepressants:
- The mechanism of action of tricyclic antidepressants in neuropathic pain is probably multimodal with contribution of reuptake of serotonin and norepinephrine inhibition, blockade of NMDA receptors and sodium channels. (8).
- Side effects include:
- dry mouth
- sweating
- dizziness, orthostatic hypotension
- fatigue
- constipation and urinary retention
- The most worrisome side effect of tricyclic antidepressants is sudden death supposedly related to cardiac arrhythmia Patients should receive an EKG before initiation of therapy to rule out QT prolonging.
- Amitriptyline:
- Frequently used in neuropathic pain in children.
- The sedating effect manifest immediately, which can be helpful as sleeping through the night is a common problem among the pediatric patient group.
- The analgesic effect may commence to occur 3 to 7 days after initiation, occasionally even later. (2)
Anticonvulsants:
- Many anticonvulsants have found a use in treating neuropatic pain.
- This may be related to the similar pathophysiology of neuropathic pain and epilepsy. Neuronal hyperexcitability characterizes both conditions. (9)
Gabapentin:
- Gabapentin mechanism is still unclear; however recent studies demonstrated gabapentin doesn’t act on gamma-aminobutyric acid (GABA) receptors or sodium channels. (9) In fact, it binds to the alpha-2-delta subunit of voltage sensitive presynaptic Calcium channels and blocks the channels both spinally and supraspinally.
- This calcium channel block modulates the release of neurotransmitters from presynaptic nerve terminals resulting in diminished excitation. (10)
- Clinically, gabapentin has been reported to be effective in the treatment of:
- neuropathic pain (including diabetic neuropathy)
- trigeminal and post-herpetic neuralgia
- pain syndromes following spinal cord injury. (11)
- Also, many studies have demonstrated that concomitant administration of gabapentin reduces postoperative pain, opioid consumption and opioid-related adverse effects after surgery. (12)
- The dose of gabapentine is increased gradually to treat neuropathic pain (over 3-4 days) as it helps to minimize sedation.
Table: Initial Dose of Gabapentine in children
Patient weight |
Dosage |
Less than 50 kg |
2 mg/kg q HS |
More than 50 kg |
100 mg q hs |
Doses are increased to twice daily (Bid) on Day 2 and to three times daily (Tid) on Day 3. Dose escalation should continue until good analgesia is achieved, side effects occur or the dosage reaches 60 mg/kg. (13)
Side effects of Gabapentin:
- Gabapentin reports lower incidence of side effects compared to the older anticonvulsivants. This drug lacks CYP-isoenzyme-mediated pharmacokinetic interactions which is a common problem with many antiepileptics and antidepressants.
- The most common adverse events include somnolence, dizziness, ataxia, fatigue, impaired concentration, edema and weight gain. (9) Allergic reaction, slurred speech, nystagmus and blurred/double vision are less frequently seen.
- Most side effects will improve over the first few days of taking the medication.
Gabapentin should not be stopped suddenly; it is usually decreased slowly over 1-2 weeks to prevent pain or withdrawal seizures.
In renal failure:
- Gabapentin should be used with caution in renal failure.
- The dose will need to be adjusted and monitored closely.
