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We read with interest the review article on alternative opioids to morphine in palliative care.1 The author has mentioned in detail various factors—biomedical, genetic, and psychological—which influence the effect of opioids. Though most of the aspects are well covered, the role of depression has not been discussed, and this has a tremendous impact on the manifestation and management of pain.2 Initial control of depression greatly facilitates pain management. Depression must be treated aggressively (for example with antidepressants and psychotherapy sessions) or pain management will remain elusive. It has also been shown that in patients who are taking opioid drugs, the bioavailability of opioids is increased with antidepressants; the tricyclic drugs are membrane stabilising, which may account for the early onset of action in patients with chronic pain.3
The author mentioned the advantages of transdermal administration of fentanyl. She noted that it is highly acceptable to patients and the patches can be applied by patients or relatives themselves. We would like to stress that 25% to 50% of patients above the age of 65 suffer from major pain problems. Age related changes in skin integrity, subcutaneous fat, and water content can affect patient response to transdermal products. In fact, fentanyl patches have been associated with death in opioid-naive older adults in doses as low as 50 μg/hour.2 Also, serum fentanyl concentrations may increase by one third in patients with a body temperature of 40°C or more. It has been suggested that fentanyl should not be given to children younger than 12 years of age or to patients younger than 18 years of age who weigh less than 50 kg. Additionally, fentanyl has a long duration of action (up to 72 hours) and therefore the side effects and adverse reactions are not easily reversed.4 In view of this, we believe that transdermal fentanyl should not be used liberally.
It was also stated by the author that tramadol is less potent than morphine and less effective for managing severe pain. However, tramadol has been used extensively and evaluated over the last 20 years. It has proved as effective as the strong opioids in acute and chronic pain settings. In particular, tramadol administration results in little respiratory depression in comparison with equianalgesic doses of opioids, such as morphine or pethidine. Tramadol has a long record of efficacy and safety, and although it should be avoided or used with caution in epileptic patients, it is now the fourth most commonly prescribed analgesic worldwide.5 It is certainly useful in the treatment of chronic, non-malignant, and malignant pain syndromes. Another considerable advantage of tramadol is its very low abuse potential. Consequently, it is not deemed a controlled (scheduled) drug.
In view of the above, we believe that tramadol has an important role as an alternative opioid to morphine in palliative care.
First, I would like to address the apparent omission of a discussion of depression. I am entirely in agreement with the respondents' comments that depression has a major role in the manifestation and management of pain. However, in this review I was considering the differential factors influencing choice of opioid, not the assessment of pain per se. I pointed out at the outset that cancer pain was multifactorial, and that a thorough assessment was a prerequisite to successful management, but that the review was of strong opioids, and was beginning from the point at which these were considered appropriate treatment. I did include the effect of antidepressants in enhancing bioavailability of opioids in the text and in table 5, but in the context of drug interactions.
With regard to transdermal fentanyl: the authors appear to imply that in beginning with a discussion of its advantages, I was advocating liberal use of this drug and route. I went on to describe all its disadvantages, including its interpatient variability and long duration of action causing potential problems of overdose. I was attempting to provide a balanced overview of a drug that has proved very popular with patients and health professionals while cautioning on its overuse.
On the question of tramadol, I do not dispute that it is an effective analgesic and has a broad spectrum of clinical use. However, both from personal practice and my review of literature pertinent to palliative care, I concluded that its efficacy in the management of progressive severe cancer pain is less conclusively demonstrated, and thus questioned its role in palliative care. Respiratory depression is rarely an issue in palliative care, nor opioid abuse, although I accept that low abuse potential may facilitate adequate analgesic prescribing in chronic non-malignant pain.