pain, drug, palliative, cancer, brussels, bordet

Medical Departments

Pain Clinic

Article 3: Pain resistant to classical treatments

Dr Dominique Lossignol (Jules Bordet Institute- Supportive and Palliative Care Unit, Brussels, Belgium)

Eighty to ninety per cent of cancer patients with pain can be controlled by the administration of the analgesic treatments proposed by the WHO.

However, it may occur that the traditional treatments prove ineffective, either because of lack of effect or because of drug-bounded side effects/toxicity (preventing to give an adequate dose), whether because of a complex clinical situation. In this case, we may talk about a potentially “uncontrollable” situation, or more exactly, of a not easily controllable situation.

A definition of work is essential.

A pain is not easily controllable when it responds partially or doesn’t respond at all to a well-conducted treatment, despite of adequate drug dosage, despite of well-chosen associations, or when increased doses have intolerable side effects without improving the analgesic effect. This clinical situation could be correlated with a syndrome.

Some clinical situations are associated to the development of pain syndromes : neoplastic brachial plexopathy (breast cancer, lung cancer), CRPS (Complex Regional Pain Syndrome), infiltration of the pelvis, and some head and neck tumors.

Movement-or-not-related breakthrough pain, chemotherapy-related (navelbine, taxol) or radiology-related pain, or pain caused by psychological troubles could be added to the abovementioned category.

The physiopathology of this kind of syndrome refers particularly to the temporal summation phenomenon and to the concept of memory for pain. Lasting electrophysiological recordings induced by a poorly-controlled pain are associated with a rearrangement of neural connections as well as with the appearance of new membrane receptors resulting from the neural “inactive” gene expression.

Distinct therapeutic approaches are proposed to meet this kind of pain. A major condition is however to insist on the importance to find a quick adequate control of pain in order to avoid that the pain evolves chronically.

1. Reduction in morphine doses and adjunction of co-analgesics

This approach supposes that some treatments still not have been proposed and does not consider the possibility of a kind of intolerance to the prescribed morphine. This attitude tested in severe pain did not prove convincing.

2. Opioid rotation

This approach is based on the incomplete cross-tolerance to morphine and is above all applied in Canada and Italy. Trials conducted in Belgium will be discussed in another session.

3. Anaesthesia approach

The use of intrathecal catheters, allows, in theory, to avoid a systemic toxicity while having a “high” analgesic effect, whatever the analgesic given alone or in association. Those catheters may be connected to a PCA pump. This supposes a localised and quite stable pain responsive of course to the proposed treatment.

The most frequent problems are : iatrogenic medullary toxicity, catheter disconnections or breakings, infections.

Data collected at the Institut J. Bordet have shown the importance to control systemic-induced supra-spinal pain, even if the intrathecal approach was optimum.

It is important to notice that the intrathecal approach is not comfortable at all for end-of-life patients.

4. NMDA inhibitors

NMDA receptors (N-Methyl-D-Aspartate inhibitors) are involved in the genesis and maintenance of chronic pain.

They are also partially responsible for the phenomenon of tolerance to opioids.

Their activation is directly related to constant pain stimulations (temporal summation) and their role in severe pain syndromes is undeniable.

Most of traditional treatments have little or no impact on the control of those receptors.

Ketamine, a non-barbiturate non morphinic anaesthetic, has been proven to be a powerful, reversible inhibitor of NMDA receptors.

At conventional doses, it is a dissociative anaesthetic drug which may induce a cataleptic-like state. There is no decrease in blood pressure nor in respiratory depression. However, Ketamine induces a difficult “waking” as nightmares or unpleasant postoperative visual hallucinations may appear.

Nevertheless, its role as inhibitor of NMDA receptors has been used to control painful clinical situations when proposed treatments were ineffective. At non anaesthetic doses, Ketamine has been reported to be effective in pain control as well as in reduction of tolerance to morphine.

Moreover, it proved to have a long-term effectiveness (sometimes for months).

Currently, its use, and more particularly as a preventive pain reliever in severe pain is being researched on large scale . An early use of Ketamine could block the whole of the processus responsible for this syndrome.

Dextromethorpan, earlier described in the session about co-analgesics, was not dealt with in this context.

Its role as a preventive remains to be demonstrated.

Finally, studies on methadone, a synthetic morphine compound, will be developed in opioid rotation.

Allegedly, this molecule, despite of its morphine effect, has an inhibitor effect on NMDA receptors.

The role of Gabapentin on the same receptors has not been proven yet in patients as this effect is usually only obtained at supra-clinic doses never reached before at conventional doses. However, results obtained in some cancer pain may consolidate its use in this field.

Conclusion

We must recognize that we remain quite powerless against uncontrollable pain. The term of not easily controllable, which also constitutes a syndrome, seem to be more judicious.

Various therapies are proposed to arrest sometimes very complex processes.

The main objective is to manage in the most optimum way every painful situation.

The use at larger scale of co-analgesics, opioid rotation, and NMDA inhibitors will probably lead to a reduced incidence of this syndrome

References:

1) Dickenson AH, Sullivan AF, Combination therapy in analgesia : seeking synergy. Current Opinion in Anaesthesiology, 6, 861-865, 1993
2) Foley KM, The treatment of cancer pain. New Engl J Med, 313, 84-95, 1985
3) Klepstadt P et al, evidence of a role of NMDA receptors in pain perception. Eur J Pharmacol, 187, 513-518, 1993
4) Lossignol DA, Ketamine and morphine in cancer pain : preliminary report. Topics on Supp Care, 6-9, 1996