Non-Pharmacological Therapy
Central Neuropathic Pain
Patient Education
- The patient should be given adequate information regarding central neuropathic pain including its underlying cause
- If the patient suffers from allodynia, application of a protective layer (eg cling film) between the skin & clothing may helpful
Painful Diabetic Peripheral Neuropathy (DPN)
Patient Education
- The patient should be educated about DPN, support should be given & expected outcomes should be reviewed
- Review mechanisms of NP, providing information on what is currently known & unknown
- Assist patient w/ practical measures (eg bed cradle to lift bedclothes off of sensitive skin)
- Patient should be made aware of how important optimal glycemic control is
- Glycemic control near normoglycemia may help slow or prevent the development of peripheral neuropathy & other complications (eg retinopathy, nephropathy, etc)
- Patients should be counseled on how to optimize their glycemic control
- Proper diet, oral antidiabetics & insulin use
- Glucose monitoring, etc
- Help patient understand that complete pain relief may not be achieved despite best efforts of patient or physician
- Inform patients of possible adverse effects from medications & any potential for abuse or development of tolerance
Optimize Glycemic Control
- Tight glucose control in type 1 DM patients helps to delay the onset of diabetic polyneuropathy & helps to slow the progression of the disease
- The benefits of intensive insulin therapy usually outweigh the risks
- It is generally agreed that any improvement in glycemic control in type 2 DM patients is beneficial
- Use tight glucose control in the elderly w/ caution as they are more susceptible to the effects of hypoglycemia
Proper Foot Care
- Patients should inspect their feet daily, use proper foot hygiene & wear proper fitting socks/hosiery that is changed daily
- Footwear
- Patients w/ neuropathy may benefit from well-fitted walking shoes or athletic shoes
- If patient has evidence of increased plantar pressure then their footwear should cushion & redistribute pressure
- Expert referral if patient suffers trauma, cellulitis or acute ischemia of the foot
Alternative Therapies
- Physiotherapy has been reported to provide pain relief in some patients
- Acupuncture has minimal but not insignificant risks
- May relieve pain &/or reduce the need for pain medications in selected patients but this method
- Transcutaneous Electrical Nerve Stimulation (TENS)
- Mild electrical stimulation through the application of surface electrodes over the painful area generates heat that relieves stiffness & improves mobility
- Interferential Therapy (IFT) uses the strong physiological effects of low frequency electrical stimulation of nerves to provide pain relief in DPN
- Spinal Cord Stimulation has high costs & risks but w/ limited evidence of efficacy
- Frequency-Modulated Electromagnetic Neural Stimulation may be helpful but w/ limited evidence of efficacy
Postherpetic Neuralgia (PHN)
Patient Education
- The patient should be given adequate information & explanation regarding PHN; this may help alleviate anxiety about the disorder
- Educate about treatment side effects
- It is important that the patient try to maintain social & physical activities
Physical Methods
- If the patient suffers from allodynia, application of a protective layer (eg cling film) between the skin & clothing may be helpful
- TENS may be helpful in some PHN patients
- Acupuncture has limited success
- Physical & occupational therapy may also have a role in treating patients w/ chronic pain
Psychological Approaches
- Cognitive-behavioral therapy (CBT), relaxation training, biofeedback & self-hypnosis techniques may help in managing intractable PHN
Trigeminal Neuralgia (TN)
Patient Education
- Inform patient about the available treatment options & the expected outcomes
Surgical Interventions
- For patients w/ TN refractory to medical therapy, early surgical therapy may be considered
- Prior to considering surgery, eligible patients should have an MRI to eliminate other causes of compression of the trigeminal nerve
- Peripheral Techniques
- Involve blocking or destruction of portions of the trigeminal nerve distal to the Gasserian ganglion
- Low morbidity but 50% have pain recurrence after 1 yr
- Percutaneous Procedures on Gasserian Ganglion
- Preferred for elderly patients, those w/ Multiple sclerosis (MS), w/ impaired contralateral hearing, & those w/ recurrent pain after microvascular decompression
- Eg radiofrequency thermocoagulation, balloon compression rhizotomy, percutaneous retro-Gasserian glycerol rhizotomy
- Microvascular Decompression
- Preferred procedure for young patients w/ typical TN
- Major neurosurgical procedure involving craniotomy to reach the trigeminal nerve in the posterior fossa
- Vessels compressing the nerve are identified & moved out of contact
- Provides longest duration of pain relief while preserving facial sensation
- Complications include aseptic meningitis, hearing loss, cerebrospinal fluid (CSF) leaks, infarcts, hematomas, transient diplopia & sensory loss
- Associated w/ 0.5% mortality rate & 3-29% facial numbness rates
- Gamma Knife Stereotactic Radiosurgery
- Least invasive procedure for TN
- Treatment option for patients w/ comorbidities, high-risk medical illness or pain refractory to prior surgical procedures
- Aims a focused beam of radiation at the trigeminal root in the posterior fossa
Top
Pharmacological Therapy
- Selection of a particular drug will depend on the experience of the clinician & patient, along w/ the expected adverse reactions
- Combination therapy may be necessary to optimize pain control
- Medications should be chosen based on their additional potential therapeutic effect
Central Neuropathic Pain
1st-line Agents
Tricyclic Antidepressants (TCA)
- Inhibit presynaptic reuptake of serotonin & norepinephrine, & block cholinergic, adrenergic, histaminergic & Na channels; block hyperalgesia induced by N-methyl-D-aspartate (NMDA) agonists
-
Administration
- Total daily dose should be given at bedtime
- Adverse Reactions
- Side effects are mostly due to antimuscarinic actions & may be decreased if started at low dose & increased gradually
- Dry mouth, constipation (may lead to paralytic ileus), blurred vision, increased intraocular pressure, urinary retention, hyperthermia, drowsiness can occur, nervousness, insomnia, headache, peripheral neuropathy, ataxia, tremor, confusion/delirium can occur esp in older patients, N/V, gastric irritation, hypotension, tachycardia, sweating, wt gain
- Special Instructions
- Start w/ a low dose to minimize side effects & titrate upward to the desired response
- Use w/ caution in patients w/ urinary retention, prostatic hyperplasia, chronic constipation, untreated angle-closure glaucoma, patients w/ CV disease, history of epilepsy, DM, impaired hepatic function
- Not recommended for elderly patients & those w/ CV disease
- Do not stop medication abruptly; taper dose over several wk
- Antidepressant therapy in children, adolescents & young adults is associated w/ clinical worsening, suicidality or unusual changes in behavior. Close observation of the patient & communication w/ the prescribing physician is warranted
Amitriptyline
- Initial dose:
- 10-25 mg PO at bedtime
- Increase dose by 25 mg/day to max dose on a wkly interval
- Max dose:
Nortriptyline
- Initial dose:
- 10-25 mg PO at bedtime
- Increase dose by 25 mg/day to max dose on a wkly interval
- Usual dose:
- 75 mg PO as single bedtime dose or divided 12 hrly
Anticonvulsants
- Bind to presynaptic voltage-gated Ca channels in the dorsal horn, resulting in a decrease in the release of excitatory neurotransmitters such as glutamate & substance P
Gabapentin
- Adverse Reactions
- CNS effects (somnolence, dizziness, ataxia, nystagmus, headache, tremor, diplopia, amblyopia); Other effects (fatigue, nausea &/or vomiting)
- Special Instructions
- Use w/ caution in patients w/ history of psychotic illness, renal impairment
- Discontinuation &/or addition or substitution of alternative therapy should be gradual over at least 1 wk
- May affect patients ability to drive or operate machinery
- Dosage Guidelines
- Initial dose:
- Day 1: 300 mg PO 24 hrly
- Day 2: 300 mg PO 12 hrly
- Day 3: 300 mg PO 8 hrly
- Based on patient response & tolerability, may increase dose in increments of 300 mg/day every 2-3 days up to a max dose of 3600 mg/day
- Max dose: 3.6 g/day
Pregabalin
- Pregabalin has higher affinity for the presynaptic Ca channel & has been shown to provide significant pain relief in chronic central NP following spinal cord injury
- Adverse Reactions
- CNS effects (somnolence, dizziness, confusion, euphoric mood, ataxia, attention disturbance, abnormal coordination, memory impairment, tremor, dysarthria, paresthesia, blurred vision, diplopia, vertigo, dry mouth, increased appetite, decreased libido, erectile dysfunction, irritability); GI effects (constipation, vomiting, flatulence); Other effect (fatigue)
- Special Instructions
- Use w/ caution in patients w/ galactose intolerance, lactase deficiency or glucose-galactose malabsorption, renal impairment, DM
- May affect patients ability to drive or operate machinery
- Initial dose:
- 150 mg/day PO divided 8-12 hrly
- May be increased to 300 mg/day after a 3-7 day interval
- May increase further to max dose after another 7 day interval
- Max dose: 600 mg/day
Other Agents
- Weak Opioid
- Low-affinity binding to µ-opioid receptors & weak inhibition of norepinephrine & serotonin reuptake
- Recommended as a 2nd- or 3rd-line treatment for central NP
- Has quick onset of pain relief & less sedative effect
- Lower risk of abuse than strong opioid receptor agonists
Tramadol1
- Adverse Reactions
- CNS effect (dizziness); GI effects (dry mouth); CV effect (vasodilation); Other effect (sweating)
- Special Instructions
- An increase risk in seizures may occur in patients taking other medications which decrease the seizure threshold
- Use w/ caution in patients w/ history of opioid dependence, seizures or at risk for seizures, increase intracranial pressure
- May cause dependence on long-term use
- Lamotrigine
- Blocks voltage-dependent Na channels inhibiting presynaptic release of excitatory amino acids
- May be considered in central post-stroke pain or spinal cord injury w/ incomplete cord lesion & brush-induced allodynia only if all other treatments fail
- Cannabinoids
- Eg Tetrahydrocannabinol, Cannabidiol
- May be considered in central pain in MS only if all other treatments fail
Painful Diabetic Peripheral Neuropathy (DPN)
1st-Line Agents
- Anticonvulsants
- Gabapentin has effective pain relief for patients w/ DPN; similar efficacy as Amitriptyline but w/ a better side effect profile
- A recent study on Gabapentin & Nortriptyline use for DPN or postherpetic neuralgia (PHN), showed significantly lower pain scores in the combination phase than for either treatment alone; Gabapentin monotherapy & Nortriptyline monotherapy were similar in efficacy
- Pregabalin provides significant pain relief & improved quality of sleep in DPN
- TCA
- Amitriptyline, Desipramine, Imipramine, Nortriptyline have been used successfully
- Typically considered 1st-line agents for painful neuropathies, including DPN, but use may be restricted by adverse effects
- Advantages of TCA include their effect on insomnia & depression which are common comorbidities in NP patients
- Baseline echocardiogram for patients >40 yr old is recommended; TCAs should not be given to patients at risk for sudden cardiac death or w/ history of CV disease
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
- Highly specific inhibition of serotonin & norepinephrine reuptake allows the availability of these neurotransmitters in the synapse
- Duloxetine is well-tolerated & not associated w/ anticholinergic side effects seen in TCA use; however, it is more expensive than TCAs
- Venlafaxine has shown efficacy in clinical trials involving DPN & mixed painful polyneuropathy
- Adverse Reactions
- CNS effects (somnolence, dizziness, insomnia, nervousness, nausea, xerostomia, wt loss, anorexia, sexual dysfunction, anxiety); GI effects (constipation, diarrhea); Other effects (abnormal dreams, yawning, tremor, blurred vision, increased sweating)
- Dose-related: vasodilation, hypertension
- Special Instructions
- Start w/ low dose to minimize side effects & titrate upward to the desired response
- Use w/ caution in renal & hepatic impairment
- Do not stop medication abruptly; taper dose over several wk
- Antidepressant therapy in children, adolescents & young adults is associated w/ clinical worsening, suicidality or unusual changes in behavior. Close observation of the patient & communication w/ the prescribing physician is warranted
- Dosage Guideline
- Duloxetine
- 60 mg PO 24 hrly
- Max dose: 120 mg/day
- Venlafaxine
- Initial dose: 37.5 mg PO 12-24 hrly
- Increase dose by 37.5-75 mg/day on a wkly interval
- Max dose: 225 mg/day
2nd- or 3rd-line Agents
- Tramadol
- Recommended by EFNS as 2nd-line treatment except for those w/ acute exacerbation of DPN, in which case it can be considered as 1st-line option
- Tramadol & Tramadol/Paracetamol combination are effective in reducing pain due to diabetes
- Use w/ caution in the elderly because of risk of confusion; it is also associated w/ increased risk of serotonin syndrome when used together w/ serotonergic drugs
- Oxycodone
- Effective in reducing pain in DPN
- Recommended as 3rd-line therapy because of concerns regarding long-term safety including potential for addiction & misuse
Other Agents
Capsaicin (Topical)
- Depletes stores of substance P from sensory nerve endings, reducing or abolishing transmission of painful stimuli from the peripheral nerve fibers to the higher centers
- Patient needs to be willing to apply 3-4 times daily & may experience initial skin irritation which typically improves in 1-2 wk
- In studies of patients w/ DPN, adjunctive therapy w/ topical Capsaicin showed better pain relief compared to its inactive vehicle comparator
- Adverse Reactions
- Local and erythema
- Other application site reactions include pruritus, papules & edema
- Dosage Guideline
- 0.0125% lotion/gel, 0.025% lotion/gel, 0.075% cream: Apply 6-8 hrly
- 0.31% gel: Apply 8-12 hrly
Lidocaine (Topical)
- Decreases neuronal membrane’s permeability to Na ions, thereby blocking the initiation & conduction of nerve impulses
- Small randomized or open-label trials have shown the efficacy of topical 5% Lidocaine transdermal patches for pain relief in patients w/ DPN, w/ minimal adverse events; significant improvement in ongoing pain, intensity of allodynia & quality-of-life measures have also been noted
- Adverse Reactions
- Mild local reactions (itching, erythema, edema)
- Rarely methemoglobinemia
- Available Strength: 5% patch
- 3 patches/day for a max of 12 hr
Alpha-lipoic acid (Thioctic acid)
- Decreases oxygen free radicals thereby influencing the underlying neuropathic process
- Studies have shown that it decreases pain, paresthesias & numbness, & has a favorable safety profile
- Adverse Reactions
- GI effects (N/V, stomach & intestinal pain, diarrhea); CNS effects (vertigo, headache); Dermatologic effects (rash, urticaria, itching); Other effects (sweating, visual disturbances)
- Special Instructions
- Should be taken 30 mins before meals
- Swallow whole, do not chew or crush
- Monitor glucose levels in urine & blood regularly
- May potentiate hypoglycemic effect of insulin or oral antidiabetics
- Advise patient to avoid alcohol intake
- 600 mg PO 8-24 hrly or
- 600 mg slow IV infusion 24 hrly x 2-4 wks or several times/wk
Benfotiamine
- Lipid-soluble thiamine derivative that studies show to have improved neuropathic pain in patients w/ diabetic neuropathy as being a transketolase activator & inhibitor of alternative metabolic pathways implicated in the pathogenesis of hyperglycemia-induced vascular damage
- Adverse Reactions
- Rarely, hypersensitivity reactions (skin eruptions, urticaria, anaphylactic reactions)
- Dosage guidelines
- Initial dose: 150 mg PO 8-12 hrly x 4-8 wks
- Maintenance dose: 150 mg PO 24 hrly
Postherpetic Neuralgia (PHN)
1st-line Agents
- Anticonvulsants
- Gabapentin & Pregabalin have established efficacy against PHN
- 1st-line agent for PHN, esp in the elderly in whom TCAs are not well-tolerated
- Gabapentin produces significant pain relief & improvement in measures of quality of life & mood
- Pregabalin has been shown to significantly decrease pain & improve sleep in randomized placebo-controlled trials (RPCT)
- TCA
- Amitriptyline, Desipramine, Nortriptyline & Maprotiline have been used successfully w/ Amitriptyline as the most widely used TCA for PHN
- Nortriptyline has been shown to be as effective as Amitriptyline but better tolerated
- Many controlled trials have shown the efficacy of TCA in PHN
- Lidocaine (Topical)
- Preferred for the elderly patients, in whom there are concerns for CNS adverse reactions from oral medications
- Five RPCTs in PHN supported the efficacy of Lidocaine patches w/ brush-induced allodynia
- Lidocaine gel (5%) has been shown to give significant pain relief in PHN for up to 8 hr
- Capsaicin (Topical)
- Provides significant pain relief but patient response can be delayed
- Discomfort & burning sensation may limit patient compliance
2nd-Line Agents
- Opioids
- Oxycodone, Morphine & Methadone have similar efficacy in PHN compared to TCA but these are associated w/ frequent discontinuation because of adverse events
- RPCTs in PHN showed that Oxycodone & Morphine provide significant reduction in pain intensity, w/ variable improvement in sleep & disability
- Tramadol
- A weak opioid & a mixed serotonin-noradrenaline reuptake inhibitor found in studies to be an alternative if first-line oral monotherapies are ineffective
If adequate pain control is not achieved using pharmacological agents discussed above, consider expert referral to a pain medicine specialist for alternative therapy
- Alternative therapy includes NMDA-receptor antagonists, intrathecal steroids, IV adenosine 5’-triphosphate, or combination therapy
Trigeminal Neuralgia (TN)
1st-line Agents
Carbamazepine
- Drug of choice for TN but efficacy may be compromised by poor tolerability & pharmacokinetic interactions
- RPCTs have shown reduction in frequency & intensity of painful paroxysms & equal efficacy for spontaneous & trigger-evoked attacks
- Adverse Reactions
- May decrease side effects by starting at a low dose & increasing slowly
- CNS effects (dizziness, drowsiness, ataxia); GI effects (dry mouth, abdominal pain, N/V, diarrhea, anorexia, constipation); Dermatologic effects [rash which may be severe, photosensitivity reactions, Stevens-Johnson syndrome, systemic lupus erythematosus (SLE)]; Hematologic effects (agranulocytosis, eosinophilia, aplastic anemia, leukopenia, leukocytosis, thrombocytopenia & purpura); Other effects (abnormalities of kidney & liver function, splenomegaly, lymphadenopathy, hyponatremia, edema, paresthesia, headache, arrhythmias, heart block, heart failure, etc)
- Special Instructions
- Avoid in patients w/ AV block, history of bone marrow depression, history of acute intermittent porphyria
- Use w/ caution in patients w/ cardiac, hepatic, renal disease or history of blood disorders
- Liver function tests (LFTs), urinalysis, blood urea nitrogen (BUN), complete blood count (CBC) should be performed prior to & periodically during the treatment
- HLA-B*1502 genetic testing is recommended to be done before starting therapy esp in patients of Asian descent; if positive, weigh in if benefit clearly outweighs risk of having Stevens-Johnson syndrome & toxic epidermal necrolysis
- Dosage Guideline
- Initial dose: 200 mg PO 6-8 hrly
- Individualize dosage titration
- Increase dose slowly to max tolerated dose
- Max dose: 1.2 g/day
Oxcarbazepine
- Typically better tolerated than Carbamazepine due to decreased potential for drug interactions
- Two RPCTs found similar efficacy of Oxcarbazepine w/ Carbamazepine on number of attacks & global assessment
If refractory to Carbamazepine & Oxcarbazepine, 2nd-line agents may be added to treatment regimen for TN 2nd-line Agents
- Adverse Reactions
- Clinically significant hyponatremia, dizziness, drowsiness, ataxia, GI symptoms (eg dry mouth, abdominal pain, N/V, diarrhea, anorexia), rash including Stevens-Johnson syndrome, weakness, abnormal gait
- Special Instructions
- Cross-sensitivity to Carbamazepine is 25-30%
- Reduce dosage in patients w/ renal impairment
- Monitor serum Na levels prior to treatment & regularly during treatment
- Enzyme-inducing effect is less than w/ Carbamazepine; when switching from Carbamazepine to Oxcarbazepine, co-medication doses may need to be reduced
- Dosage Guideline
- 600-1800 mg/day PO in divided doses
2nd-line Agents
- Lamotrigine has been reported in a study to be efficacious in TN & may also be effective as add-on therapy
- Other anticonvulsants (eg Clonazepam, Gabapentin, Phenytoin & Valproate) have been suggested in small open-label studies to have therapeutic benefit for TN but evidence remains insufficient to support or refute their efficacy
Phenytoin
- Adverse Reactions
- Side effects may decrease w/ dose reduction or continued administration
- GI effects (N/V, abdominal pain & lack of appetite), CNS effects (headache, dizziness, insomnia); Other effects (hirsutism, gum tenderness, gingival hyperplasia, coarsening of facial features, mild hypersensitivity w/ skin rash (typically erythema multiforme w/ fever)
- Prolonged administration may result in subtle changes in mental function & cognition. Rickets & osteomalacia have occurred & may have been caused by interference of Vit D & folate metabolism
- Phenytoin toxicity may result in nystagmus, diplopia, slurred speech, ataxia, confusion & hyperglycemia
- Rarely Stevens-Johnson syndrome, SLE or erythema multiforme, blood disorders eg thrombocytopenia, leukopenia, etc may occur
- Special Instructions
- Use w/ caution in patients w/ liver dysfunction, DM
- Assess compliance or possible toxicity by routine Phenytoin serum level monitoring during dose adjustment
- Therapeutic serum conc: 40-80 mmol/L
- Monitor for signs of blood or skin toxicity; patient should inform physician immediately if signs of blood toxicity occur eg fever, sore throat, bruising, skin rash, etc
- Initial dose:
- 100 mg PO 8 hrly
- May increase gradually to 200 mg 8 hrly if necessary
- Max dose:
Baclofen
- Special Instructions
- Use w/ caution in patients w/ impaired renal function, stroke, convulsive disorders, peptic ulceration, elderly patients w/ cerebrovascular disorders, resp, hepatic or renal failure, underlying bladder sphincter hypertonia, psychiatric disorders
- Avoid abrupt discontinuation
- Start with 5 PO mg 8 hrly for 3 days,
- Increase to 10, 15 & 20 mg 8 hrly at 3-day intervals
- Max dose: 80 mg/day
OTHERS
- Adverse Reactions
- Oral: loss of appetite, nausea, diarrhea, GI upset
- Inj: hypersensitivity reactions, pain, induration at IM sites, headache, sweating
- 0.5 mg PO 8 hrly or
- 0.5 mg IM/IV 3x/wk
- Adverse Reactions
- GI effects (N/V, abdominal pain, diarrhea); Hypersensitivity reactions (sweating, tachycardia, pruritus, urticaria)
- Special Instructions
- Use w/ caution in patients w/ allergy to cobalamins, intolerance to thiamine, sugars (ie glucose-galactose malabsorption, Lapp lactase deficiency, sucrose-isomaltase insufficiency)
- Available Strength:
- Vitamin B1 250 mg, B6 250 mg, B12 1000 mcg
- Dosage Guideline
- Initial dose: 1 tab PO 8-12 hrly x 7-10 days
- Maintenance dose: 1 tab PO 24 hrly
- Available Strength:
- Vitamin B1 100 mg, B6 200 mg, B12 200 mcg
- Dosage Guideline
- Initial dose: 1 tab PO 8 hrly
- Maintenance dose: 1 tab PO 24 hrly
Not all products are available or approved for above use in all countries.
Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information.
Specific prescribing information may be found in the latest MIMS & MIMS.com
Brands available in:
Hong Kong
Indonesia
Malaysia
Philippines
Singapore
Thailand
Vietnam
Top