ADJUVANT ANALGESICS

The IAHPC Manual of Palliative Care
2nd Edition

III. PAIN CON'T

Table of Contents

The adjuvant analgesics

• are not analgesics in the true pharmacological sense, but may contribute significantly to pain relief when used either alone or in combination with other analgesics
• they are of particular use for opioid-insensitive pain, particularly neuropathic pain
• include
  • corticosteroids
  • drugs for neuropathic pain
    • antidepressants
    • anticonvulsants
    • oral local anaesthetic agents
    • NMDA receptor antagonists
  • drugs for bone pain
  • bisphosphonates
  • anxiolytic
  • psychotropic drugs
    • neuroleptics
    • anxiolytics
    • psychostimulants
    • cannabinoids
  • muscle relaxants
    • benzodiazepines
    • baclofen
    • dantrolene
      

Corticosteroids

Drugs for Neuropathic Pain

• antidepressants are indicated for the treatment of neuropathic pain
• they act by blocking the presynaptic re-uptake of serotonin and noradrenaline in the central nervous system, enhancing the action of the descending inhibitory pathways
• the character of the neuropathic pain does not determine whether a response will occur
  • there is no evidence that antidepressants are more effective than other agents for the burning dysaesthetic type of pain
• compared to the antidepressant action, the analgesic effect of tricyclic antidepressants (TCAs)
  • is usually seen with lower doses (e.g. 50-100 mg/d amitriptyline)
  • occurs more quickly (response should be evident within 5-7 days)
  • has been documented in patients with no features of depression
• a TCA (amitriptyline, imipramine or doxepin) is started at a dose of 10-25 mg at night, increasing to 50-100 mg
• if there is no benefit in one week the drug is stopped
• there is considerable individual variation in patients' responses to different drugs, and a trial of a second antidepressant is sometimes successful
• TCAs are probably more effective at relieving neuropathic pain than the newer antidepressants, but have double the rate of adverse effects
  • drugs that affect both serotonin and noradrenaline re-uptake [serotonin noradrenaline re-uptake inhibitors (SNRIs, e.g. venlafaxine) and noradrenergic and specific serotoninergic antidepressants (NSSAs, e.g. mirtazepine)] are likely to have greater analgesic effect than selective serotonin re-uptake inhibitors (SSRIs)
• The adverse effects of TCAs (sedation, anticholinergic effects and postural hypotension) are usually mild when used in low dose for neuropathic pain, but may nevertheless be troublesome in palliative care patients.
  

• anticonvulsants are indicated for the treatment of neuropathic pain
• they act by suppressing the spontaneous neuronal discharges and neuronal hyperexcitability that occur after nerve injury and may also have a central effect
  • the character of the neuropathic pain does not determine whether a response will occur
• there is no evidence that anticonvulsants are more effective than other agents for the shooting lancinating type of pain
• drugs used frequently are gabapentin, carbamazepine, sodium valproate and clonazepam.
  • gabapentin may be no more effective than carbamazepine, but causes less troublesome adverse effects (17)
• the dose and the initial titration are the same as for anticonvulsant therapy
  • there is no data relating blood levels and analgesic activity
• the dose is increased step-wise until a response occurs or toxicity ensues
  • serum levels can be checked and the drug should be stopped if there is no response when the levels are in the therapeutic range for anticonvulsant therapy
• there is considerable lack of cross-resistance between the drugs and treatment with a second anticonvulsant is sometimes successful
• the adverse effects of the different anticonvulsants are similar, with gastric intolerance (nausea and vomiting), sedation, ataxia, dizziness and confusion being the most common
  • carbamazepine can cause leucopenia and the white blood cell count should be checked periodically.
    

• are indicated for neuropathic pain refractory to other therapy
• act by neuronal membrane stabilization by sodium channel blockade, probably at both peripheral and central sites
• lignocaine infusions (2-5mg/kg IV over 30 minutes) can be used to predict whether there will be a response to mexiletine
  • lignocaine infusions (IV or SC) may be useful for rapidly controlling severe neuropathic pain
• mexiletine is the preferred oral local anaesthetic-type drug
  • it is commenced at a dose of 150 mg/d and increased by 150mg each few days up to a maximum of 750 mg/d
  • the dose and blood levels of mexiletine do not correlate with pain relief
  • it must be given with particular caution to patients with ischaemic heart disease or cardiac arrhythmias
• the adverse effects of mexiletine include dizziness, sedation, tremor, and unsteady gait; nausea and indigestion can be lessened by taking the medication with food.
  

• are indicated for the treatment of refractory neuropathic pain and other severe pain when opioid tolerance is a concern
  • the NMDA (N-methyl D-aspartate) receptors in the spinal cord are activated by continuing stimuli in nociceptive afferents, leading to sensitization of the dorsal horn cells and causing perpetuation of the sensation of pain and reduced opioid sensitivity
  • this mechanism is believed to underlie opioid tolerance and the relative opioid-insensitivity of neuropathic pain
  • the NMDA receptor antagonists ketamine, dextromethorphan and methadone inhibit this process
• ketamine is a dissociative anaesthetic used for short surgical procedures
  • subanaesthetic doses has been shown to improve the effect of opioids in relieving refractory neuropathic pain or other opioid-insensitive pain
  • it can be given PO, IV or by CSCI
  • is usually started at 100mg/d and titrated up by 100mg/d, up to 500mg/d
  • 2 RCTs of ketamine therapy in patients with advanced cancer have been assessed in a Cochrane review (19)
  • adverse effects: psychotomimetic effects, may be treated or prevented by the co-administration of a benzodiazepine or haloperidol
    • more likely if titration too rapid, liver metabolism is slowed or the oral route is used

Adjuvant drugs for bone pain

1. Bisphosphonates

• are chemical analogues of pyrophosphate that inhibit bone resorption
• are effective in the treatment of hypercalcaemia associated with cancer
• have been shown to reduce pain and skeletal events in patients with bone metastases
• act by inhibiting osteoclast activity, blocking mineral dissolution
• the more recently introduced nitrogen-containing bisphosphonates (pamidronate, ibandronate, olpadronate and zoledronic acid) are more potent than the non-nitrogen-containing compounds etidronate and clodronate
• systematic and Cochrane reviews of the RCTs of bisphosphonate therapy indicate that there is improvement in the pain related to bone disease that occurs over time (9, 10, 20, 21, 22)
• there is insufficient evidence to recommend bisphosphonates for immediate analgesia, but they should be considered if analgesics and radiotherapy provide inadequate control

2. Radioisotope

• the systemic administration of the bone-seeking radioisotope, 89-Strontium, is effective in controlling pain related to bone metastases
• it is preferentially taken up in osteoblastic metastases, which show increased uptake on bone scan
• improved pain control is reported in up to 80% of patients
• responses are usually evident 2 to 3 weeks after treatment and last for 3 to 6 months
• compared to local radiotherapy, strontium reduces the number of new pain sites for about four months following treatment
• the main adverse effect is myelosuppression, which is usually mild and not clinically significant
  • there must be adequate haematological reserve before treatment is given
• about 10% of patients suffer a transient flare reaction with increased pain following treatment, which settles spontaneously

Psychotropic drugs

1. Neuroleptics

• standard neuroleptic drugs (e.g. chlorpromazine, haloperidol) have no analgesic action
  • aid treatment of pain by reducing anxiety and improving night-time sedation
  • same benefits can be obtained with a benzodiazepine, without the potentially troublesome anticholinergic and extrapyramidal side effects, unless the neuroleptic drugs are specifically indicated for the treatment of delirium or nausea
• levomepromazine (methotrimeprazine) has been shown to have analgesic action
  • the analgesic activity of 20mg levomepromazine is approximately equivalent to 10mg morphine
  • may be useful if further increase in opioid dose is undesirable
  • adverse effects: sedation and postural hypotension

2. Anxiolytics

• benzodiazepines
  • e.g. diazepam, oxazepam and lorazepam
  • aid treatment of pain by virtue of their anxiolytic effect
  • also useful for muscle spasm or acute musculoskeletal pain
  • adverse effects: sedation, weakness and postural hypotension

3. Psychostimulants

• methylphenidate
  • does not have an analgesic action
  • can be used to counteract severe sedation caused by opioids
  • adverse effects: dysphoria, tolerance and dependence

• cannabinoids are no more effective than codeine in treating pain
• adverse effects of cognitive impairment and sedation limit their use

Muscle relaxants

• benzodiazepines
  • effective for muscle spasm
  • main adverse effects are weakness and sedation
• baclofen
  • acts at a spinal level
  • started at 5mg/d and cautiously titrated against effect up to a maximum of 100mg/d
  • main adverse effects are weakness and sedation
  • must be withdrawn slowly to avoid withdrawal syndrome and seizures
• dantrolene
  • acts directly on muscle
  • started at 25mg/d and titrated against effect to a maximum of 400mg/d
  • main adverse effects are weakness, sedation and hepatotoxicity

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