pain, drug, palliative, cancer, brussels, bordet

Medical Departments

Pain Clinic

Article 2: Co-analgesics

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

The use and effectiveness of co-analgesics in cancer pain is widely accredited, especially since the publication of the WHO analgesic ladder in 1986.

These drugs are a complement to the usual analgesic treatments (NSAIDs, weak and strong morphine treatments) : they are a priori not used as pain relievers and belong to distinct pharmacological categories.

Any drug that has a demonstrated favourable impact on pain may be considered as a co-analgesic.

Some molecules, when combined with opioids may have a synergic effect.

Find hereunder the main co-analgesics :

1. Tricyclic antidepressants

These molecules (amitriptyline, imipramine, desipramine for example) block the reuptake of both serotinin and noradrenalin. And have an analgesic effect in neuropathic pain. Because of its anticholinergic properties, amitriptyline must be used with caution (dry mouth, urinary retention). Sedation and orthostatic hypotension may also occur.

Initial dose for amitriptyline : 25mg orally.

A lower supply is provided in neuropathic pain than those required in the treatment of depression.

There is no link between serum level and clinical response.

You may also be given desipramine or chlomipramine, but fewer data are available than for amitriptyline.

The so-called “new” antidepressants such as paroxetine and vinlaflaxine did not demonstrate a significative co-analgesic effect.

Studies with duloxetine (Cymbalta) demonstrated a favourable effect on neuropathic pain.

2. Anti-epileptics

Carbamazepine (Tegretol) and diphenylhydantoine are usually recommended in smaller doses than for anticonvulsive treatments. These molecules have a delayed effect : they become efficient within 4 to 5 days.

Their action is not well known : it is thought to involve neural membrane stabilization ( peripheral activity), but a central action is not excluded.

The starting dose for carbamazepine is 200mg orally, but may be increased gradually in accordance with the clinical response (400-600mg daily).

It’s useful to note that carbamazepine belongs pharmacologically to tricyclic antidepressants.

Because of its lower toxicity, Valproate or valproic acid (Depacon) is also indicated in the treatment of trigeminal neuralgias.

Gabapentin (Neurontin) is a new anti-epileptic agent, however, its definite modes of action remain unclear. It is believed to interact with central nervous system- located receptors, distinct of those implicated in the treatment of convulsions. ( GABA, Glycin, benzodiazepine).

There is no enzyme induction at hepatic level nor effect on the blood formula, contrary to carbamazepine.

Because of its efficiency in the treatment of some neuropathic pains (zona, diabetes), Gabapentin could be indicated in cancer pain, and clinical studies are convincing to indicate the molecule as a first-choice.

Recently, pregabaline became available with the same indications as gabapentine. Its pharmacological profile and its efficacy appears to be more suitable for neuropathic pain.

3. Benzodiazepine

These molecules are indicated for their myorelaxant effects, and sometimes for their anticonvulsant properties. Their anxiolytic effect is interesting, but it is difficult to consider anxiolysis like a “co-analgesic” particularity.

Diazepam or clonazepam are the “core molecules” . The enzyme induction at hepatic level has to be taken into account. Its use should not be prolonged.

4. Steroids

Steroids are widely used and have multiple indications in oncology and algology.

They are frequently used for cerebral oedema or epidural metastases, with or without compression of the spinal cord, at a 4X4mg dose for dexamethasone.

Steroids are indicated for the particular case of liver metastases as well as for neoplastic infiltration of the peritoneum.

Their chronic use as analgesics is limited because of their side effects (gastro-intestinal ailment, diabetic decompensation, amyotrophy…). However, for end-of-life patients, those side effects don’t have to be taken into account.

5. Amphetamine

The use of dextroamphetamines at a 10mg dose potentiates the effects of morphine for the treatment of postoperative pain. The chronic use in cancer patients must be studied.

The combination of methylphenidate with opioids may have a synergic effect in some cases.

6. Caffeine

This molecule strengthens the NSAIDs and morphine effects. Its combination with anti-migrainous drugs originating from ergot of rye is known but the effect we are looking for is mainly biological (increased intestinal absorptive efficiency).

The molecule has shown a favourable effect on cephaleas at a 50-100mg orally, especially for post lumbar puncture cephaleas.

7. Antiarrhythmic and antihypertensive drugs

Mexiletine may be proposed in the treatment of some neuropathic pains as well as for CRPS Type I and Type II. (Complex Regional Pain Syndrome)

Because of its negative inotropic effect, this molecule is of little interest.

Clonidine is used for its alpha 2- mimetic properties.

This agent is of great interest especially in anaesthesiology, but very little in chronic cancer pain.

8. “NMDA” Inhibitors

This group of drugs belongs in theory to the category of co-analgesics. In fact, these molecules block the stimulating effects of the NMDA receptors (N-Methyl-D-Aspartate inhibitors). This receptor sits on the surface of some brain cells and bone marrow cells. This receptor is responsible for the phenomenon of temporal summation of pain and could intervene in the genesis and aggravation of chronic pain.

Various molecules may be used in clinical routine.

Ketamine (Ketalar),a non barbiturate anaesthetic, has already proven to be effective in cancer pain.

Another molecule, dextromethorphan, which is largely used as a cough suppressant, may also be used as a pain reliever.

A pharmacological speciality combining dextromethorphan and morphine at equivalent doses is now available.

This combination is not justified by pharmacological data, particularly regarding low dosages.

Amantadine , an antiviral and antiparkinson drug, has also shown to be an inhibitor of NMDA receptor, but promising laboratory data were not confirmed when the drug was tented in clinical trials.

Surprisingly, methadone, a synthetic opioid, is said to have an inhibitor activity on those receptors. That is why this molecule is indicated for opioid rotation.

Notice that Gabapentin as an antiepileptic has also an inhibitor effect on NMDA receptor.

9. Cannabis-derived drugs

Documentation is poor on cannabinoids’ modes of action. The identification of endogen cannabis-derived agents could lead to potential therapeutic uses, unexplored till now.

Studies were conducted on delta-9-tetrahydro-cannabinol (THC) . The analgesic profile of THC suggests a synergic effect with opioids and prospective randomised studies indicate a safe profile. Cannabinoids are effecive in central neuropathic pain syndromes (like multiple sclerosis) and peripheral neuropathic pain syndromes as well. THC is delivered through a spray (Sativex) .

Notice that both Nabilone and dronabinol are in use in UK and USA respectively.

The current situation (legislation, lack of clinical studies) reminds us of morphine’s background, but this is not an argument to limit our knowledge.

Conclusion

The concept of co-analgesics is in full progress, and still more new molecules are added to this category.

This shows how complex mechanisms are in chronic cancer pain.

Co-analgesics are mainly used in neurogenic pain, but more complex situations may also benefit from those treatments.

However, these substances open new doors in algology.

References
1) Who. Cancer pain relief and palliative care. Geneva : Who, 1996
2) Portenoy RK. Adjuvant analgesics in pain management. In : Doyle D, Hanks GWC, Mac Donald N (Eds). Oxford Textbook of Palliative Medicine. Oxford Medical Publications, 1993.
3) Bruera E, Ripamonti C, Adjuvants to opioid analgesics. In : Pavy R, ed. Cancer Pain, 1993
4) Lossignol D, Mancini I, Plehiers B, et al, Successful treatment of neuropathic cancer pain with gabapentine, Support Care Cancer, 8, 2000