To know the most commonly used adjuvants in pain management, their indication for use and common side effects associated with them.
To recognise their place in the management of acute pain
Adjuvants and other drugs
This article aims to inform on some of the most commonly used adjuvants. Adjuvants have traditionally been used for the management of chronic pain, however, they are increasingly being used within the acute care setting for managing those with chronic painful conditions undergoing acute procedures and to assist in patients who have difficult to manage acute pain i.e. those who are opioid-tolerant.
Entonox is a mixture of 50% oxygen and 50% nitrous oxide. It is effective for acute procedural pain and in emergency situations. It has a rapid onset and is also excreted rapidly so that as soon the patient stops inhaling the mixture, the effects wear off within seconds. The patient administers the mixture him or herself as it is a form of patient controlled analgesia and its safety lies in the fact that is administered by the patient. Entonox is extremely safe to use as long as it is used in appropriate patients. Although some patients feel dizzy, drowsy or feel sick, no other side effects are experienced. It should not be given to patients who have or are suspected of having a pneumothorax, in cases of bowel obstruction, those with severe head injuries or in decompression sickness as nitrous oxide diffuses rapidly into gas-filled spaces increasing the size of them. It is especially useful for short painful procedures such as dressing changes.
Ketamine has been available for clinical use as an anaesthetic for more than 30 years and its analgesic properties in subanaesthetic doses were recognised early on. Ketamine is a non-competitive NMDA-receptor antagonist and there is a highly significant correlation between pain relief and serum concentrations of ketamine. Analgesia is obtained by 1/10 to 1/5 of an anaesthetic dose and this would lead to concentrations that are likely to block a substantial fraction of NMDA receptors . Ketamine, at subanaesthetic doses, can produce visual and auditory disturbances, cognitive impairment, disturbed proprioception, feelings of unreality, hallucinations, mental disturbances and discomfort . Recently, ketamine is being increasingly used for the management of acute pain in those patients who have difficult to manage pain i.e. opioid-tolerant patients and opioid-dependant patients with a good degree of success.
Pain states associated with injury or disease affecting the peripheral or central nervous system (neuropathic pain) remain among the most difficult to treat of all the chronic pain syndromes . Antidepressants are widely used to these painful conditions and also to manage irritable bowel syndrome, temporomandibular joint dysfunction, atypical facial pain and fibromyalgia.
Tricyclic Antidepressants (TCAs) were the first medication category proven effective for chronic neuropathic pain in double blind, placebo controlled trials. Contrary to the assumption of the initial trials, pain relief and relief of depression are independent effects . While every blinded clinical trial of TCAs has found them efficacious (, ) it is not the case with the non TCAs and yet the latter would be safer to give with less side effects. The reason for the apparent analgesic superiority of TCAs is the presumed mechanism underlying antidepressant activity. Until such time that research has shown that non TCAs are more superior to TCAs, Rowbotham et al  offers these guidelines:
If a TCA is tried at doses producing blood levels in the therapeutic range (for depression) without pain relief, the available literature would suggest that other TCAs, SSRIs and MRIs are also likely to fail.
If a TCA relieves the patient’s pain but the side-effects prove intolerable, the non-TCAs should be tried in the hope of finding one that is analgesic with fewer side-effects.
Starting with the newer non-TCAs and switching to TCA only if pain is not relieved is a valid approach.
Patients with safety contraindications to TCAs or intolerable side effects at subtherapeutic doses of TCA should be given a trial of a non TCA before abandoning this drug category.
The most common TCA in use is amitriptyline although clomipramine, desipramine, doxepin etc have all been used.
Epilepsy and neuropathic pain have several parallels beyond the usefulness of anticonvulsant drugs for some pain symptoms following nerve injury . For instance, epileptic seizures are triggered by the hyperexcitability of neurones in the brain and can be spontaneous, recurrent, or paroxysmal, similar to nerve injury pains. Pain and epilepsy result from excess neuronal activity and therefore both can be treated by either blocking excitability or increasing inhibitions to balance the hyperexcitability. Evidence for increased excitability in many cases of neuropathic pain which can be less responsive to conventional analgesia therapy has prompted the use of alternative agents (Dickenson and Chapman 2000).
Evidence indicates that novel substrates contributing to the etiology or neuropathic states are sensitive to membrane stabilising drugs such as the anticonvulsant carbamazepine . Review of clinical studies indicate that carbamazepine is well established in the treatment of trigeminal neuralgia and may also be considered as a primary agent for other types of nerve injury pains . Gabapentin is a newer anticonvulsant and is thought to interact with calcium channels in that the so-called gabapentin-binding protein is associated with a subunit of the calcium channel (Taylor et al 1998). Recent evidence suggests that newer anticonvulsants drugs such as gabapentin and pregabalin may offer an alternative therapeutic approach. Gabapentin is an antiepileptic drug that has analgesic activity in neuropathic pain states of varying origins . Lamotrigine is a novel antiepileptic agent that inhibits the release of glutamate, possibly by stabilising the neural membrane through blocking activation of voltage sensitive sodium channels (Cheung et al 1992). Luria et al (2000) have shown that in a randomised, double blind, placebo controlled study lamotrigine offered dose related analgesia which was significantly superior to placebo for patients with refractory painful diabetic neuropathy. Unfortunately, lamotrigine and carbamazepine have serious side-effects (blood, hepatic and skin disorders) which limit their use.
Capsaicin is an alkaloid derived from chillies. There is evidence that capsaicin can deplete substance P in local nerve sensory terminals and it is substance P that is through to be associated with initiation and transmission of painful stimuli. Topically applied capsaicin is useful in alleviating the pain associated with diabetic neuropathy, osteoarthritis and psoriasis . The NNTs for some improvement are 4.2, 3.3 and 3.9 respectively . These may not be the most effective treatments, for example, oral anticonvulsants are more effective in diabetic neuropathy. Current evidence on the use of capsaicin in postherpetic neuralgia and post-mastectomy pain is based on very small numbers.
There is significant interest in the use of cannabinoids for pain management. Much of the effect of these drugs is anecdotal and given the tight legislation surrounding its use, many patients take the drug illegally. Campbell et al  in a qualitative systematic review found that cannabinoid derivatives tested in cancer, chronic non-malignant or acute pain proved no better than the least effective analgesics but with many adverse events including psychotropic adverse events. However, the trials included in the systematic review were not exceptionally large nor particularly well designed.
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