Year : 2008 | Volume
: 52 | Issue : 4 | Page : 367-
Potentiation of Opioid-Induced Analgesia by L-Type Calcium Channel Blockers: Need for Clinical Trial in Cancer Pain
S Basu Ray1, Raj D Mehra2,
1 Additional Professor in Anatomy, Department of Anatomy, All India Institute of Medical Sciences, New Delhi - 110029, India
2 Professor in Anatomy, Department of Anatomy, All India Institute of Medical Sciences, New Delhi - 110029, India
S Basu Ray
Department of Anatomy, All India Institute of Medical Sciences, New Delhi - 110029
Previous reports indicate that the analgesic effect of opioids is due to both closure of specific voltage-gated calcium channels (N- and P/Q-types) and opening of G protein-coupled inwardly rectifying potassium channels (GIRKs) in neurons concerned with transmission of pain. However, administration of opioids leads to unacceptable levels of side effects, particularly at high doses. Thus, current research is directed towards simultaneously targeting other voltagegated calcium channels (VGCCs) like the L-type VGCCs or even other cell signaling mechanisms, which would augment opioid-mediated analgesic effect without a concurrent increase in the side effects. Unfortunately, the results of these studies are often conflicting considering the different experimental paradigms (variable drug selection and their doses and also the specific pain test used for studying analgesia) adopted by researchers. The present review focuses on some of the interesting findings regarding the analgesic effect of Opioids + L-VGCC blockers and suggests that time has come for a clinical trial of this combination of drugs in the treatment of cancer pain.
|How to cite this article:|
Ray S B, Mehra RD. Potentiation of Opioid-Induced Analgesia by L-Type Calcium Channel Blockers: Need for Clinical Trial in Cancer Pain.Indian J Anaesth 2008;52:367-367
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Ray S B, Mehra RD. Potentiation of Opioid-Induced Analgesia by L-Type Calcium Channel Blockers: Need for Clinical Trial in Cancer Pain. Indian J Anaesth [serial online] 2008 [cited 2020 Feb 18 ];52:367-367
Available from: http://www.ijaweb.org/text.asp?2008/52/4/367/60650
Though essential for survival, pain is a distressing sensation. It has been defined by the International Association for Study of Pain (IASP) as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." Pain is associated with disability, depression and a poor quality of life. Besides, loss of capacity for productive work is also an important consideration in our country. Thus, effective treatment of pain, particularly chronic cancer pain, is of utmost necessity. Acute pain has been defined by the IASP as "Pain of recent onset with limited duration and usually due to injury or disease." Pain, which persists even after the normal time of healing, is considered chronic. More generally, pain persisting for more than 3 to 6 months is described as chronic.
History of pain treatment
Application of lotions containing balsam, rose oil and sal ammoniac and even hot oil were prevalent for treating pain before the 16 th century. Ambroise Pare (1510-1590) advocated proper cleaning of wounds and ligation of ruptured blood vessels for better pain relief  . He also introduced the concept of pain relief during surgery, which was contradictory to the prevalent thinking that pain was associated with attainment of salvation  . In fact, when James Simpson used chloroform to relieve the pain of childbirth, it was thought by the clergy that "Chloroform is a decoy of Satan, apparently offering itself to bless women; but in the end it will harden society and rob God of the deep, earnest cries which arise in time of trouble, for help."
Merits and demerits of morphine as an analgesic
Opioids like morphine are commonly used for the relief of pain though their administration produces side effects like nausea, oversedation, constipation, pruritus and urinary retention , . Still higher doses lead to respiratory depression, which can prove life-threatening (and may be career-threatening for doctors). Thus, researchers are searching for adjuvants to opioids, which would increase the analgesic effect of opioids without a corresponding increase in its side effects. Examples of such drugs are N-methyl, D-aspartate (NMDA) receptor antagonists like ketamine and anticonvulsants like gabapentin , . Probably, the most extensively investigated group of drug are the blockers of L-type voltage-gated calcium channels (L-CCBs). These are further divided into three major groups - dihydropyridines (e.g. nifedipine, nimodipine), phenylalkylamines (e.g. verapamil) and benzothiazepines (e.g. diltiazem) (for discussion  ).
Voltage-gated calcium channels - types and their role in neural transmission
Voltage-gated calcium channels (VGCCs) are ion channels situated on the cell membrane of the neuron, which open in response to an action potential and permits the influx of calcium ions  . Calcium ions are unique and vitally important second messenger system within neurons. The various types of VGCCs are the N-, P/ Q-, R-, L- and T-types. The calcium ions entering through these channels might either mediate the release of neurotransmitters into the synaptic cleft or produce short- or long-term changes in the cell signal transduction mechanisms. L-type channel (also known as Ca V 1) has been further divided into Ca V 1.1, 1.2, 1.3 and 1.4 sub-types  . Among these, the Ca V 1.2 subtype is predominantly expressed by neurons and is believed to regulate synaptic plasticity and gene expression ,.
Importance of L-calcium channel blockers in opioid analgesia
The rationale for using L-CCBs along with opioids is that the latter blocks N- and P/Q-types of VGCCs in neurons, expressed on presynaptic nerve terminals and does not seem to have any effect on the L-VSCCs  . Presumably, concurrent closure of L-VGCCs, which are located on postsynaptic terminals, would increase the analgesic effect of opioids. However, it needs to be remembered that the effect of opioids on VGCCs is an indirect one, mediated by the â ã subunits of G proteins, which are downstream to mu-opioid receptors.
In the following paragraphs, certain relevant studies in humans have been described in detail which is followed by a discussion of results of our studies on laboratory animals.
Voluntary human studies on acute pain - a veritable maelstrom
Many of the studies investigating the combined analgesic effect of opioids and L-CCBs have noted increased morphine-like analgesic effect, both on experimental animals ,, and humans ,,. In humans, this is reflected by the decreased requirement of opioids (opioid-sparing effect). Significantly, L-type calcium channel blockers (L-CCBs) do not have any analgesic action by itself  . However, very high doses of diltiazem (300 or 500 mcg) and verapamil (300 or 500 mcg) have been reported to produce analgesia in rats after intrathecal administration  .
Zarauza et al 2000 compared the therapeutic efficacy of morphine in combination with nifedipine or nimodipine - both L-CCBs or magnesium sulphate (an antagonist of the NMDA receptor) in the treatment of postoperative pain  . Though, pain at rest was not reduced by these drugs, morphine + nimodipine significantly decreased pain produced by movement on the 3 rd postoperative day only. Nimodipine (30 µg.kg -1 .h1 ), which was administered by intravenous infusion for a period of 20 h beginning immediately after post-anaesthetic induction, did not produce any episode of hypotension. However, in a more recent study on patients undergoing knee replacement surgery, nimodipine was noted to increase morphine requirement during the postoperative period (first 48 h)  . In this study, nimodipine was given by the oral route (90 mg 1 h before surgery followed by 30 mg every 6 h for 48 h after surgery). These patients received spinal analgesia (2.5 -3 ml of 0.5% hyperbaric bupivacaine) followed by patient controlled analgesia (1 mg morphine bolus dose with 5 min lockout period). At the time of leaving the recovery room, patients also received 0.05 mg.kg -1 of morphine, intravenously. Pain was assessed in these patients by moving the operated knee at 2, 4, 6, 8, 12, 24, and 48 h after surgery. Though the study showed that co-administration of L-CCBs could be counterproductive, the authors of this report also mentioned that the results might have been affected by the route of administration/dose of nimodipine. This appears to be so, since oral nimodipine is reported to have a high first-pass metabolism  . Also, the correct oral dose of nimodipine is 240 mg.kg -1 .day -1 in four divided doses, which is higher than that administered to the patients in the study, probably for avoiding hypotension. In contrast to this, in a different study, Carta et al 1990 had reported that administration of slow-release preparation of nifedipine (20 mg tablets) at 2 pm and 11 pm on the day before and at 7 am on the day of surgery significantly increased the analgesic effect of morphine during the postoperative period  . No serious side effect was observed during surgery apart from a slight decrease in the systolic blood pressure.
In an experimental study on human volunteers, verapamil (2.5 - 10 mg) was able to potentiate the analgesic effect of morphine (10 mg), when co-administered by rapid intravenous infusion  . Pain was produced by noxious finger pressure and by immersion of the hand in ice cold water. Side effects noted were a brief period of tachycardia along with a small fall of blood pressure. It is important to remember that verapamil does not cross the blood brain barrier in contrast to both nifedipine and nimodipine, implying a peripheral site of action. For that matter, even the analgesic effect of opioids has been reported to have both a centrally- and a peripherally-mediated component  . Thus, L-CCBs could enhance opioid-mediated analgesia by peripheral mechanisms too.
A Study on the Primate
In a different but extremely interesting study, effort was made to separately assess analgesia and respiratory depression after co-administration of diltiazem and morphine  . The study was based upon the hypothesis that L-CCBs could potentiate both the analgesic as well as the respiratory depressant effect of opioids. For this, the experiment was conducted in rhesus monkeys (n=14) of either sex. Respiratory parameters were measured by the pressure-displacement plethysmograph. The results showed that the respiratory rate, minute volume and tidal volume was depressed independently by morphine (both bolus dose of 3.2 mg.kg -1 and cumulative 0.3 - 10 mg.kg -1 s.c.) and fentanyl but without been modified by diltiazem (40 mg.kg -1 i.m.). The results also showed that diltiazem was able to selectively potentiate the analgesic effect of morphine but not of fentanyl (the reason was not known). Analgesia was estimated by the warm-water tail-withdrawal assay at 50 o C in the experimental subjects. Also, it needs to be noted that diltiazem can actually cross the blood-brain barrier. However, direct application of nimodipine + sufentanil on to the ventral surface of the medulla in cats readily potentiated the respiratory depressant effect of sufentanil  . Overall, it appears that diltiazem could selectively increase the analgesic effect of morphine.
Side effects of L-calcium channel blockers
It is particularly important to be aware of the side effects of L-CCBs because intravenous infusion of nimodipine has been reported to produce significant hypotension in some cases, which was refractory to simple volume loading or to low doses of inotropes  . Moreover, oral nimodipine (60 mg every 4 h) could also lead to sinus arrest  .
Clinical trials on cancer patients
The results of certain clinical trials in humans (not in India) already exist (for a short discussion on these, please refer to our recent publication  ). In one such trial, the analgesic effect vs. side effect of morphine + nimodipine combination in cancer patients was evaluated  . Both the drugs were administered through the oral route. Oral nimodipine (120 mg.day -1 ) was noted to significantly reduce the daily requirement of morphine, provided the patients have been already on morphine therapy for some period of time. The incidence of hypotension was also relatively less (about 8%) in this study.
Studies on laboratory animals correlated with an earlier study in human
Finally, regarding the suitability of writing a review article by us could be questioned (anatomists by profession with more than a passing interest in neuropharmacology), the subsequent part of this article deals with some of the exciting results observed in our laboratory on rodents. We selected nimodipine for our study because previous research indicated that it  -
Was more lipophilic than other L-CCBs and thus capable of crossing the blood brain bar rierWas more effective than many other VSCC blockers in inhibiting Ca uptake by neuro blastoma cellsDecreased the release of substance P from neurons of the dorsal root gangliaInhibited the release of glutamate from synaptosomes prepared from cerebral cortex andDilated cerebral blood vessels at much lower doses than that required for peripheral vasodilatation (cerebroselective).
Initially, the acute analgesic effect of morphine + nimodipine was studied after a single administration of each of these two drugs (morphine was given by subcutaneous and nimodipine by intraperitonaeal injections)  . The analgesic effect did not differ significantly between the two groups (statistical analysis was done using ANOVA). Following this, the analgesic effect was observed after chronic administration  . Nimodipine (2mg.kg -1 intraperitoneal administration, once daily) was combined with morphine (10 mg.kg -1 twice daily subcutaneously) for 10 days (The doses might appear to be very high to clinicians but in rodents, it is not so, as their metabolic activity is roughly seven times higher than in humans). The results were different in that the analgesic effect of morphine was potentiated between days 4-10 by nimodipine as compared to the group receiving morphine alone, even 12 h after its administration (both in the morning and evening). This has never been reported earlier. The result could also be interpreted in that tolerance to morphine was slow to develop in the nimodipine + morphine treated group. Next, the same dosage schedule of nimodipine was combined with a higher-escalating dose of morphine (20 mg.kg -1 s.c. twice daily for 7 days followed by 30 mg.kg -1 of morphine between days 8-14 days). Significant elevation of analgesic effect was noted only on days 11 and 12. These data point to the fact that a moderate dose of nimodipine (2 mg.kg -1 once daily which is less than the doses used by many other investigators in rats) could enhance the analgesic effect of morphine on chronic administration only. With reference to the specific LCCB to be used for a proposed clinical trial, diltiazem would be safer for reasons mentioned earlier.
With regard to the intrathecal route, ours was the first study to investigate the acute analgesic effect of morphine + nimodipine in rats  . The analgesic effect of intrathecal morphine (5µg) + nimodipine (5µg) showed earlier onset and a more prolonged analgesia than morphine (5µg) alone. Surprisingly, on reviewing the literature, we noted that nimodipine has been administered in humans (n=2) suffering from cancer pain, by the epidural route  . It is surprising because drugs are first tested on experimental animals and then on humans but in the case, the opposite happened. In this study by Filos et al (1993), epidural morphine (3 mg) was combined with intravenous infusion of nimodipine (2 mg.h -1 ). The analgesia resulting there of was of longer duration than that from epidural administration of 10 mg of morphine alone (synergism or potentiation). Again, epidural nimodipine (2 mg bolus + 2 mg.h -1 infusion) alone produced analgesia of a shorter duration. This is similar to the findings in our study where intrathecal nimodipine alone produced transient analgesia, which quickly reached baseline by 30 min of its administration  .
Can these results be explained by present day scientific literature on the molecular mechanisms of pain transmission in the nervous system? In a recent report, L-type VGCCs have been shown to be critically responsible for mediating wind-up, a form of short-term plasticity in nociceptive neurons, which results from repetitive activity in the pain transmitting neurons  . This results in enhanced pain sensation like hyperalgesia and allodynia, mediated by N-methyl, D-aspartate (NMDA) receptors. Possibly, blockade of L-CCBs might attenuate this process of wind-up and central sensitization and facilitate the analgesic effect of opioids.
In conclusion, more clinical trials are necessary to determine the efficacy of this combination of drugs. Proper selection of subjects would be necessary with reference to cardiovascular functions as certain rapidacting L-CCBs like nifedipine have been noted to be harmful in post-myocardial infarction patients ,. Since our studies did not find significant analgesia after acute administration of this combination of drugs, it would be better to evaluate it in patients of chronic pain, preferably cancer pain. The route of administration could be oral. Intrathecal administration in terminally ill cancer patients with chronic pain could be considered though pharmaceutical preparations containing nimodipine for intrathecal administration is not commercially available. All this would also help to assess the efficacy as well as the margin of safety of different L-CCBs in combination with opioids like morphine. The next step could be the evaluation of these drugs in other types of chronic pain. Definitely, a sigh of relief from these patients will be sufficient reward for the efforts.
Acknowledgement: Financial support from the Indian Council of Medical Research, New Delhi is gratefully acknowledged.
Conflict of Interest: I along with my co-investigators have filed an All-India patent for "Ananalgesic combination of morphine and nimodipine" in 2004.
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