i) Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for 150 years in Europe, and probably for a great deal longer in the East, in the form of willow bark extract. Useful when given appropriately, examination of the chronic pain population indicates that a very high number of patients are intolerant to these drugs because of gastrointestinal or other side-effects. There are two possible hypotheses for this. Firstly, chronic pain sufferers tend to be somewhat hypochondriacal and intolerant of body symptoms in general and thus less tolerant of real or perceived side-effects when taking medication. The second is that there may be a sub-group of patients whose pain is not managed well early on. NSAIDs may produce side-effects, limiting their use. With no pain relief, the patient fails to exercise. This hampering of their rehabilitation because of inadequate analgesia may contribute significantly towards the chronicity.
Recently COX2 antagonists have come on the scene, but the first wave of these have been disappointing in the UK, in that the side-effect profile does not appear to be particularly better than the present drugs (Meloxicam, Etodolac). The newer drugs, Vioxx and Celebrex, are now available in the USA and will soon become available in Europe. Their arrival is awaited with eager anticipation, but the results may prove to be disappointing. The products may not be as side-effect free as they first seem.
ii) The use of opioid drugs for the management of chronic non-malignant pain is fraught with difficulties, some real and some perceived. Morphine itself has tended not to be prescribed for chronic pain, because of a fear or stigma concerning Morphine. Physicians may fear dependence, tolerance and side-effects. There is a wide difference of opinion, which is still to be resolved; however, some patients can have their pain adequately controlled with opioids, without an unacceptable level of addiction problems. The potential risk of addiction remains a very real problem for a minority. Also, a significant number of patients with chronic pain complain of bothersome side-effects from medication. Mobility and distress must be monitored and benefits must accrue in both these parameters, as well as in reduction of pain.
iii) In the UK and in the USA, traditionally most patients with chronic pain receive an opioid derivative such as Codeine, Dihydrocodeine or Dextropropoxyphene. In the past Pentazocine and Buprenorphine enjoyed a passing vogue but are now little used. Pentazocine proved to have unacceptable side-effects, and Buprenorphine, originally thought to be non-addictive, was shown to have addictive potential and since being classified as a controlled drug has enjoyed little popularity. Nefopam has limited efficacy and popularity, and Meptazinol is short-acting, and often associated with an unacceptable level of side-effects.
Recent work suggests that Codeine and Dihydrocodeine are merely pro drugs for Morphine, and exert their action through metabolism to this compound. Given that a significant number of the population do not have the metabolic pathway to facilitate this, it is not surprising that there is a significant failure rate to produce any analgesia at all and that patients getting analgesia seem to get limited relief-hence possibly the popularity of these preparations being compounded with Paracetamol. There is good evidence that in some patients, much of the analgesic effect in these combined preparations lies with the Paracetamol itself, whilst many of the side-effects lie with the opioid.
v) Tramadol hydrochloride is an orally active, clinically effective, centrally-acting analgesic. It can produce analgesia that has been compared to Codeine or Dextropropoxyphene. It has been used in post-surgical pain, obstetric pain, cancer pain and chronic pain of mechanical and neurogenic origin. Analgesic tolerance is not a significant problem, and psychological dependence and euphoric effects are minimal. There are a significant number of patients in the chronic group who develop side-effects, but many of those who tolerate the drug get useful benefit in pain reduction. This slow-release formulation is an appropriate vehicle for chronic pain management.
Tramadol has an affinity, albeit relatively weak, for mu opioid receptors. It is also a neuronal uptake inhibitor. The monoamine neurotransmitters 5HT (Serotonin) and Noradrenaline (NA) are involved in the inhibition of spinal cord dorsal horn neurone responses to painful stimulation (i.e. closing the gate). Analgesia can result from activating the pain inhibitory pathways originating from higher CNS levels, and containing these neurotransmitters. Tramadol inhibits the uptake of 5HT and Noradrenaline but not Adenosine, Cyclic AMP, Dopamine, or Gaba.
Metanalysis by Moore and McQuay indicates an appropriate dose response curve for Tramadol, and suggests a reduced number needed to treat to show therapeutic efficacy as compared with Codeine, in doses of 75 to 150 mg. Nausea, vomiting and dizziness are greater than with Codeine, somnolence about the same and constipation much less. In the chronic pain situation nausea and vomiting are attenuated with usage, as is somnolence for both drugs, but constipation remains a particular problem with Codeine and Dihydrocodeine, and less of a problem with Tramadol.
Side-effects from Tramadol can be minimised by starting with a low dose and increasing gradually. There is evidence that this reduces the side-effects and improves tolerance. According to need, it can be started in a low dose of 50 mg daily or twice a day, and gradually titrated to reach 50 mg three times a day by day 3. Once a patient is established on a therapeutic dose, they can be put on the slow-release formulation to provide round-the-clock analgesia.
B. PSYCHOACTIVE DRUGS.
i) Anticonvulsants are well acknowledged as being effective in the management of shooting pain, for example: trigeminal neuralgia and the shooting element of neurogenic pain, such as post-herpetic neuralgia, diabetic neuropathy and similar conditions. Carbamazepine appears to be the most effective drug although there is a higher incidence of side-effects than with Sodium Valproate. Recently Gabapentin and Lamotrigine are enjoying popularity, either as “add on” drugs, or as sole agents. Further drug development of these types of agents might produce useful efficacy in the future.
ii) Tricyclic antidepressants are one of the most commonly used analgesics in pain clinics. This is not for the specific antidepressant action, but is more associated with the activation of pain inhibitory pathways. This appears to be less of a feature with the tetracyclic agents, and has meant that their usage in chronic pain has as yet remained unproven. This is of course is disappointing as the side-effect profile is significantly better. The sedative effect of Amitriptyline can be harnessed to good usage by giving the tablet one or two hours before retiring, and it should not be used during the day.
ANALGESIC PAIN MANAGEMENT
In general, patients with pain can be given a trial of Paracetamol. An appropriate non-steroidal can be used if there is an inflammatory process, and continued if these are effective and if side-effects are minimal. The next optimal step in the analgesic ladder will be the use of agents like Tramadol, Dextropropoxyphene, or Dihydrocodeine, with long-acting preparations being ideal for chronic pain. At present, slow-release Tramadol would appear to be the most effective drug in chronic pain for this group of patients. If side-effects preclude its usage, one of the other agents can be considered.
Finally a small group of patients might be suitable for the use of opioids themselves.
In conjunction with this ladder, anticonvulsants and tricyclic antidepressants can be considered, for their specific and appropriate actions on shooting and burning pain, usually of neurogenic origin.