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Pain Unit

Article 1 : Treatment of pain (actual data)

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

 

Opiate rotation

Opiate, and especially morphine, are still now at the centre of the treatment of cancer pain.
When correctly used, morphine allows to control the major part of painful syndromes present in oncology, that it is or not associated with peripheral analgesic (AINS, paracetamol) or with co-analgesic (antidepressant, antiepileptic drugs, muscle relaxant, etc.)
Its pharmacology and its bioavailability make it interessant for a practical point of view. Moreover, its cost is weak in comparison with its therapeutic benefits. Nevertheless, this drug has side effects and is toxic.
Indeed, constipation and nausea are very common. Even if these problems are limited to the first days of the treatment, it is important to give the patient a diet or a laxative treatment. Otherwise, there will be a major digestive obstruction.

Moreover, undesirable side effects are also common such as sedation, faintness/lipothymy , myoclonus , a confusional syndrome that can lead to delirium, visual, auditory, sensitive hallucinations, a digestive intolerance or simply an incomplete control of pain despite strong opiate doses. These complications are linked to the apparition of active metabolites , the morphine-3-glucuronide, the morphine-6-glucuronide and the normorphine.
The morphine-3-glucuronide is involved in central hyperexcitability and in hyperalgesia . It is also involved in the appearance of myoclonus and of convulsive crises. These disorders are more frequent when there is a renal failure or dehydration.
Consequently, it is possible to find another efficient therapeutic solution, and, naturally, without side effects. Moreover, the individual answer to morphine can be very various from a patient to another and a toxicity can always appeared even with an appropriate treatment, independently from the underlying painful syndrome.
It is time to think of using another morphine compound. Moreover, there is no crossed intolerance between opiate known as "strong", as the clinical experiment shows it, putting back the stress on the concept of "resistance to morphine".

Recently, the discovery of under-units within "mu" receivers has reinforced this observation by giving him a molecular substrate. This leads to the notion of "opiate rotation", particularly known in Canada and in the United States but also in Italy.
The molecules implied in this concept are morphine, methadone, fentanyl, hydromorphone and oxycodone.

In practice, the methadone was the substance that granted the more attention in the field. Methadone is a synthetic morphine compound that acts on the "mu" receivers and, contrary to morphine, on "delta" receivers.
Moreover, it could had an inhibiting effect on the NMDA receivers (N- Methyl-D- Aspartate) involved in phenomena of morphine compound tolerance and in phenomena of memorization of pain (see article).
Thanks to its pharmacological profile, it makes part of the morphinics with an average duration of action (half-life of 8 to 10 hours). No active metabolite is known. Methadone can be injected orally or by rectal suppository. Its bioavailability is estimated between 41 and 99 percent (88 percent in average). Moreover, it has a biphasic elimination.

Methadone cost is weak.
However, there is a phenomenon of accumulation that can appear when one uses it for too long (this phenomenon is called "resevoir"). This accumulation seems to be a problem when the equivalency has not been respected.
Indeed, the initially accepted conversion factor between morphine and methadone was 1:1. For the morphinics, this data is based on observations realized on "naïve patients".
The more important use of methadone has allowed to revise this ratio which is currently situated between 10:1 and 15:1.
It seems that the early morphine dose have an impact on this factor (Ripamonti) but the data on this subject remains partial.
The clinical applications of methadone in cancerology concern the controlled pain, what requires important doses of morphine. It also concerns situations with morphine, neurological (sleepiness, substantially) or digestive intolerance and eventually, the existence of a neuropathic compound of pain.
The conversion modalities involved in the rotation are largely based on clinical observations and reflect conversion factors between morphinics and the incomplete crossed tolerance between them.

One thinks then of reducing the equivalent dose by about 30 percent to respect this phenomenon, and of acting during three days (72 hours) by applying a conversion factor of 10:1. Methadone will be injected every eight hours.
Nevertheless, we have to see that some people have had rewarding results after a quick change, 24 hours, by passing from morphine to methadone, by applying a conversion factor of 5:1.
However, we cannot forget the time necessary to the elimination of active metabolite. They can indeed interfere with the methadone action.
The purpose was essentially the antalgic control. To do so, it is useful to follow the patient in order to prevent a pain recrudescence.

The experience acquired in Bordet Institute affirms the importance of opiate rotation in case of morphine or other opiate toxicity. However, we applied a conversion factor of 10:1 during three days, by controlling that the patient gets inter-doses when he wants.
Even if we respect these factors, it is clear that the patient answer will lead the doses adaptation.
The results confirm its favourable effects on pain control, on diminution of side effects with neurological compound (confusional syndrome, hallucinations, myoclonus) but also digestive intolerance.

An improvement of cognitive functions has also been observed.
This data allows to analyse by another way the concepts of morphine-resistant pain or morphine-semiresponsive pain.
Indeed, these notions have often been used to object or to postpone a morphinics treatment but now, it seems that these arguments can no longer be used such as in the past.

Moreover, it is interesting to see that since medical personnel can transcutaneously used fentanyl, it is easier to pass from a strong morphinic to another. This often leads to the improvement of pain symptomatology, whatever the sense of rotation can be.
Passing from morphine to fentanyl and vice versa can be considered as a "rotation". In the same way, passage of a level II morphinic to a level III morphinic is more or less a rotation, even if in this particular case, the changing is based on an inappropriate antalgic control.

Finally, we have to mention the importance of using coanalgesic when there is an inappropriate pain control, by considering its intrinsic characteristics, but this action risks to be impossible if morphinics have a neurological toxicity. At this time, the pain assessment is made more difficult and the coexistence of toxic metabolites and of psychotropic medication could have a deleterious impact on the upper functions.
The question is to know if it is necessary to wait for the appearance of a central toxicity to envisage opiate rotation or if a systematic using of the concept allows to stop them or even to make them dissapear.
Studies have to be done in this field.
Opiate rotation is an action based on clinical observations but also on fundamental research. It is an interesting answer to opiate toxicity problem. The identification of the conversion factors, of the application modalities but also of the procedure to follow remain points that have to be studied.

References
1) Mercadante S : Opioid Rotation for Cancer Pain. Cancer 1999, 86:1856-1866.
2) Bruera E, Pereira J, Watanabe S, Belzile M, Kuehn N, Hanson J : Opioid Rotation in Patients with Cancer Pain. Cancer 1996, 78:852-857.
3) Ripamonti C, Bruera E : CNS adverse effects of opioids in cancer patients : Guidelines for drug treatment. CNS Drugs 1997, 8:21-37.
4) Smith MT, Watt JA, Cramond T : Morphine-3-glucuronide : a potent antagonist of morphine analgesia. Life Sci 1990, 47:579-80.
5) Ripamonti C, De Conno F, Groff L, et al : Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: Comparaison of two clinical experiences. Ann Oncol 1998, 9:79-83.
6) Ripamonti C, Groff Liliana, Brunelli Cinzia, Polastri D., Stavrakis A., De Conno F : Switching from morphine to oral methadone in treating cancer pain : What is the equianalgesic Dose ratio? J Clin Oncol 1998, 16:3216-3221.
7) Mercadante S, Casuccio A, Calderone L : *Rapid Switching from Morphine to Methadone in Cancer patients with poor response to Morphine. J Clin Oncol 1999,17:3307-3312.

Other Articles:
- Coanalgesics
- Resistant Pain
- Tables

 

Person in charge : Dr. Lossignol Dominique