alpha(2)-adrenergic agonists for regional anesthesia - A clinical review of clonidine (1984-1995)

Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.

alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role.

Although the vast majority of patients with cancer pain receive effective analgesia from standard therapy, a few patients, particularly those with neuropathic pain, continue to experience severe pain despite large doses of systemic or intraspinal opioids. Animal studies suggest intraspinal alpha 2-adrenergic agonists may be effective in such cases. Eighty-five patients with severe cancer pain despite large doses of opioids or with therapy-limiting side effects from opioids were randomized to receive, in a double-blind manner, 30 micrograms/h epidural clonidine or placebo for 14 days, together with rescue epidural morphine. Pain was assessed by visual analog score (VAS), McGill Pain Questionnaire, and daily epidural morphine use. Success was defined as a decrease in either morphine use of VAS pain, with the alternative variable either decreasing or remaining constant. Blood pressure, heart rate, and degree of nausea and sedation were monitored. Successful analgesia was more common with epidural clonidine (45%) than with placebo (21%). This was particularly prominent in those with neuropathic pain (56% vs. 5%). Pain scores were lower at the end of the treatment period in patients with neuropathic pain treated with clonidine rather than placebo, whereas morphine use was unaffected. Clonidine, but not placebo, decreased blood pressure and heart rate. Hypotension was considered a serious complication in 2 patients receiving clonidine and in 1 patient receiving placebo. This study confirms the findings from previous animal studies which showed the effective, potent analgesic properties of intraspinal alpha 2-adrenergic agonists and suggests that epidural clonidine may provide effective relief for intractable cancer pain, particular of the neuropathic type.

Epidural clonidine analgesia for intractable cancer pain

In a randomized, double-blind crossover study, 40 patients with postherpetic neuralgia were given single oral doses of clonidine, 0.2 mg, codeine, 120 mg, ibuprofen, 800 mg, or inert placebo. Pain relief and side effects were recorded for 6 hours. Patients reported significantly more relief after clonidine than after the other three treatments. Codeine and ibuprofen were ineffective. Sedation, dizziness, and other side effects were more frequent after clonidine (74%) or codeine (69%) than after placebo (36%) or ibuprofen (28%). Reported pain relief was greater during trials in which side effects were present. A single, mild side effect was associated with as much additional pain relief as multiple, severe side effects. Clonidine's superiority to codeine, which had a similar incidence of side effects, argues for a specific analgesic effect. In addition, side effects may have contributed to clonidine analgesia, perhaps by suggesting to patients that they had received a potent drug.



Clinical Pharmacology and Therapeutics (1988) 43, 363–371; doi:10.1038/clpt.1988.44

Association of pain relief with drug side effects in postherpetic neuralgia: A single‐dose study of clonidine, codeine, ibuprofen, and placebo

The prime function of anaesthetists is to relieve pain. The technical skills and pharmacological knowledge required to do this during surgery place them in an ideal position to treat pain in other situations. Thus anaesthetists have been at the forefront of developments in the relief of pain during labour and devote much attention to the relief of chronic pain of whatever aetiology. Indeed, active societies exist in both these disciplines and have been vigorous in the promotion of research and teaching, even though such activities are expensive in terms of time and manpower. Postoperative pain relief, however, has been sadly ignored [189] and members of the public [114], and even eminent members of the profession [67,162], have been moved to comment on the severity of pain after surgery and the lack of efforts to relieve it. The standard method of prescribing a fixed dose of opioid to be given at limited time intervals, and with administration being delegated to a nurse, is manifestly a totally inadequate method of producing postoperative analgesia. Extradural block with local anaesthetic agents will abolish postoperative pain, but its use has been limited by anxiety about hypotension, tachyphylaxis, systemic toxicity, the technical difficulty of insertion of a catheter into the thoracic extradural space and the problems of postoperative surveillance. Other nerve blocks, particularly intercostal [125], can also be very successful, but their use is restricted by the feasibility of repeating them in the postoperative period. Patient controlled analgesia was introduced in an attempt to overcome many of these problems and has proved to be a successful method after surgery [39, 182]. It can also be used as a method

Daniel Lachance

Papers

Intrathecal Morphine ToleranceUse of Intrathecal Clonidine, DADLE, and Intraventricular Morphine