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Anesth Analg 2003;97:1474-1478
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Does a Single Intravenous Injection of the 5HT3 Receptor Antagonist Ondansetron Have an Analgesic Effect in Neuropathic Pain? A Double-Blinded, Placebo-Controlled Cross-Over Study

Gary J. McCleane, MD, Rie Suzuki, PhD*, and Anthony H. Dickenson, PhD*

Rampark Pain Centre, Lurgan, Northern Ireland, and the *Department of Pharmacology, University College, Gower Street, London

Address correspondence and reprint requests to Gary McCleane, Rampark Pain Centre, 2 Rampark, Dromore Road, Lurgan, BT66 7JH, N. Ireland, UK. Address email to gary{at}mccleane.freeserve.co.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Neurokinin–1-expressing neurones in lamina I to III of the spinal cord are intimately involved in the regulation of ascending and spino-bulbal pathways that regulate excitatory transmission. In experimental animals, ablation of these neurones reduces the responses to a variety of nociceptive stimuli. Furthermore, in animals, spinal application of the selective 5HT3 receptor antagonist ondansetron mimics these effects, indicating that 5HT3 receptors play a pronociceptive role and mediate descending excitatory controls that allow spinal neurones to fully code peripheral stimuli. In this study, we examined the potential analgesic effect of a single IV injection of ondansetron in humans with chronic neuropathic pain. Each consenting subject received a single IV injection of 8 mg ondansetron and placebo in varying order at least 1 wk apart with pain scores being recorded for the 48 h preceding and after each injection. Pain scores were significantly reduced 2 h after ondansetron injection (but at no other time point). This suggests that ondansetron can have an analgesic effect in neuropathic pain. Side effects were minor and infrequent.

IMPLICATIONS: The selective 5HT3 receptor antagonist ondansetron, currently used as an antiemetic, may also have analgesic properties. Side effects with a single IV injection are infrequent and usually mild.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Frequently relatively minor peripheral activity or a brief noxious stimulus is associated with a prolonged and intense nociceptive response. This phenomenon may be associated with an imbalance in the normal inhibitory and excitatory processes within the central nervous system. Much emphasis has been given to peripheral and central spinal excitatory systems, but it is becoming clear that the brain can also drive pronociceptive activity. If an intervention could be made that prevented these neuronal responses then both the intensity and duration of subsequent nociception may be reduced.

Interest has recently focused on the Neurokinin 1 (NK1) expressing neurones within lamina I–III of the spinal cord. These neurones are thought not to make extensive arborizations within the spinal cord but to be predominately nociceptive-specific projection neurones that terminate within the parabrachial area and the brainstem with limited termination in the periaqueductal gray area, thalamus, and reticular formation (1–4). We have recently provided evidence (5) for a strong link between lamina I projection neurones and their supraspinal targets and their involvement in pain processing. In particular, we have evidence for a role for 5HT3-mediated descending facilitation in the enhancement of central spinal pain processing that not only determines how spinal neurones respond to peripheral inputs but also suggests that changes in this system underlie chronic pain states such as neuropathy.

By deletion of lamina I, NK1–receptor-expressing neurones using saponin conjugated to substance P we have shown that as peripheral inputs arrive in lamina I, the neurones rapidly inform the parabrachial area (PB) and other areas of the brainstem implicated in affective, autonomic, and emotional responses to pain. In addition, the PB can connect to other areas of the brainstem that project back down to the spinal cord, thus completing this loop (5). There is now evidence that these descending pathways cause powerful excitatory drives back onto the spinal cord through activation of descending 5HT neurones (6–8) that target 5HT3 receptors in the spinal cord. These spinal-brainstem-spinal loops are not only needed for the full coding of polymodal peripheral inputs by spinal neurones but are enhanced after nerve injury. Thus a hierarchy of separate but interacting excitatory systems exist, at peripheral, spinal, and supraspinal sites that all converge on spinal neurones. In animal studies, a lesion of the NK1 expressing spinal neurones causes changes in the responses of spinal cord neurones that are mimicked exactly by spinally applied ondansetron (5) and replicate certain responses seen in animals with genetic knockout of the 5HT3 receptor (9). Saponin-substance P treatment also reduces the numbers of 5HT containing neurones in the brainstem activated by peripheral noxious stimulation (5). Because much of the 5HT3 receptor localization at spinal levels is on the terminals of afferent fibers (9), ondansetron is likely to reduce the loop by a block of excitability of afferent fibers and thereby reduce nociception.

These findings fit with the literature that 5HT3 receptors have a pronociceptive function (9–11). Based on these hypotheses a 5HT3 receptor antagonist (ondansetron, Zofran, GlaxoSmithKline, Research Triangle Park, NC) should alter the coding of noxious stimuli in a number of pain states. The aim of this study was to investigate the possible analgesic effect of ondansetron in human neuropathic pain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This is a double-blinded, placebo controlled cross-over study of 26 consenting adult patients with chronic neuropathic pain (all had pain for more than 1 yr) of mixed etiology that was unresponsive to currently available opioid analgesics, nonsteroidal antiinflammatory drugs (NSAIDs), tricyclic antidepressants (TCA), and anticonvulsants. Neuropathic pain was presumed when more than 3 of the cardinal symptoms (i.e., burning pain, paresthesia/dysesthesia, shooting/lancinating pain, numbness and allodynia) were present. Regional Ethical Committee approval was obtained before initiation of the study and permission from the United Kingdom Medicines Control Agency obtained to use a drug outside its licensed indication.

Pain was measured using an 11-point Likert scale (0 = no pain, 10 = most amount of pain imaginable). Overall pain, burning pain, paresthesia/dysesthesia, shooting/lancinating pain, and numbness and allodynia were assessed using this scale twice hourly for the 48 h before each treatment (baseline) and for the 48 h after treatment. If the recording interval occurred during a period of sleep, it was omitted. Concomitant analgesic consumption for each 48-h period was also recorded along with a record of the number of hours slept and the number of times sleep was interrupted by pain on the night before and after treatment were recorded. Quality of sleep and activity levels were also recorded using a Likert scale. These variables were recorded first thing in the morning after the night in question. Subjects were also asked to note side effects.

Each subject received a single IV injection of ondansetron 8 mg and a similar volume of saline (4 mL) in varying order separated by at least 1 wk. Each solution was colorless and of similar viscosity and was administered into an antecubital vein through a 25-gauge needle. On each occasion a baseline and treatment set of pain scores and ancillary data were recorded.

Changes in pain scores between baseline and treatment were recorded for each of the 2-h intervals after treatment with ondansetron and placebo. Mean changes were calculated and compared using Student’s t-test at individual time points and entire treatment periods compared using analysis of variance techniques. Significance was assumed with P values <0.05. Overall average sores were calculated for both baseline phases to ensure equality in overall pain before study treatment.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Twenty-three subjects provided completed results. Two failed to attend all of their study visits and one withdrew consent before administration of any study medication. The demographic characteristics of the participants are shown in Table 1, and the occurrence of the component symptoms of neuropathic pain in Table 2.


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  		Table 1. Demographic Characteristics of Completed Subjects
 

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  		Table 2. Numbers of Subjects with Component Symptoms of Neuropathic Pain
 
The overall mean pain scores for all subjects in the pre-placebo baseline phase was 6.52 (95% confidence intervals ± 0.91) as compared with 6.35 (95% confidence intervals ± 0.93) during the entire preactive treatment baseline phase. This difference was not statistically significant and demonstrates equality in pain levels before each trial drug administration. There was no significant change in pain scores between the baseline and active treatment 48-h periods. However, when individual time points were considered, a significant change in overall pain scores was observed at the t + 2 h period after ondansetron administration. At this time the mean pain scores were 1.17 lower (95% confidence limits ± 0.89, P < 0.02) than during a similar time during the baseline phase. At this particular time point pain scores were recorded at the same time during both the baseline and active treatment periods to eliminate the possibility of a diurnal variation in the pain. At no other time after placebo or ondansetron administration were there significant changes in pain scores. The change in pain scores for the component symptoms (burning, paresthesia/dysesthesia, numbness, shooting/lancinating pain and allodynia) are shown in Table 3. A number of subjects obtain marked, if short-lived, relief after ondansetron injection and requested continued oral dosing after study completion.


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  		Table 3. Changes in Pain Scores From Baseline to Treatment and From Placebo to Active Treatment
 
There were no changes in concomitant analgesic consumption, activity, or sleep duration or quality. Reported side effects were light-headedness immediately after ondansetron injection in one subject (with no decrease in blood pressure), urticarial rash again immediately after ondansetron injection in one subject, and headache in two others in the hours after active drug treatment (Figure 1).



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  		Figure 1. Single intravenous dose of ondansetron 8 mg versus placebo in 26 human subjects with chronic refractory neuropathic pain. Mean pain scores (Likert scale) recorded every 2 h for 24 h after administration of placebo or ondansetron 8 mg.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The intention of this study was not to definitively state whether a 5HT3 antagonist has indisputable antinociceptive effects. Fulfilling this goal would require a larger oral dosing study where the drug in question is administered over a longer period of time. Rather, it was to assess whether the data collected in animal models of pain using SP-SAP and ondansetron had a potential human application. This study would suggest that there is an impression of an antinociceptive effect with ondansetron that merits further human investigation. This need for further study is even more appropriate because ondansetron is a relatively old drug, extensively used, with a proven antiemetic effect (12) and a well-defined and minor side effect profile.

The overall reduction in pain scores was relatively modest, although in some subjects a much more impressive reduction was observed. Any reduction in a cohort of subjects who had been previously resistant to conventional treatments (e.g., opioids, NSAIDs, TCAs, antiepileptic drugs) merits attention. It seems that ondansetron has a more marked effect on the overall perception of pain than on the constituent symptoms. We lack animal models of paresthesia/dysesthesia, lancinating/shooting pain, and burning pain. In animals, ondansetron reduces responses to static mechanical stimuli but is more effective against larger von Frey forces than smaller ones. It reduces heat responses (but to a lesser degree than mechanical responses) and does not alter wind-up, although it is effective against prolonged peripheral chemical and inflammatory inputs. Thus, the profile of the drug may confer differential effects on various symptoms of neuropathic pain seen in humans. Thus, actions of ondansetron may help to define, in general terms, which drugs are most effective for each of the component symptoms observed in subjects with neuropathic pain and define mechanisms behind these symptoms. Further studies with sensory testing may aid this goal.

The initial intention was to study 30 subjects, but the study was abbreviated for ethical reasons. When each subject completed their portion of the study, their blinding code was broken and they were given the opportunity to request continued oral treatment if they had had relief with the IV formulation of the drug. Unfortunately a number of subjects were refused prescription of the medication by their family doctor in view of its cost (approximately £250 or $375 US per month). It was therefore deemed inappropriate to subject further participants to the application of placebo and active treatments when, if they derived benefit from active treatment, they would be denied further access to it.

Relief was noted at the 2-hour stage after active treatment. With a single IV injection steady-state plasma levels would not be achieved and therefore the potential maximum effect of the drug may be much greater. Ondansetron penetrates the blood-brain barrier relatively poorly (13), and animal studies have used direct spinal routes of administration (10,11). It is possible that with sustained regular dosing a more prolonged and consistent level of analgesia could be achieved. The lack of change in sleep duration and quality, and the absence of a difference in number of concomitant analgesics taken, is likely to be a function of the relatively short duration of analgesia. Thus, by bedtime the analgesic effect, if present, would have worn off with a return to normal background pain.

The finding of an antinociceptive effect is in keeping with the finding of an analgesic effect with other 5HT3 antagonists; granisetron can produce analgesia in subjects with fibromyalgia pain (14–16) and alosetron in female subjects with diarrhea predominant irritable bowel syndrome (17–19). The major side effects associated with the use of a 5-HT3 receptor antagonist are headache and constipation. In the case of alosetron severe constipation has been observed along with reports of ischemic colitis (20) to the extent that its prolonged use is questioned (21). Side effects were infrequent in this study but may be more apparent when the drug is given on a more prolonged basis.

Although the laboratory evidence suggests an effect mediated through 5HT3 receptors on neurones at the spinal cord level, there is also the suggestion that ondansetron has a sodium channel blocking effect (22–24). However, animals with a genetic deletion of the 5HT3 receptor show a profile against formalin-induced nociception that is indistinguishable from that seen with ondansetron. From a clinical perspective, the knowledge of how a drug works is less important than the clinical intensity of its effect and its likelihood of producing side effects. Nevertheless it is informative that the animal data are supported by the human clinical findings and that the use of a 5HT3 antagonist may allow a very specific block of a particular defined nociceptive receptor. We have tended to use drugs with a myriad of pharmacological effects (and often side effects). The greater understanding of the pathophysiology of pain processing may therefore produce benefits of more targeted and specific pharmacological treatment. Given the evidence that blocking of 5HT3 receptor interrupts a complex spinal-brainstem-spinal loop (5), the interactions between ondansetron and other drugs such as opiates and NK1 receptor antagonists that posses receptors associated with this pathway merits further study.

The animal data would also suggest that prior administration of SP-SAP or ondansetron prevents the increase in pain and sensitivity that often accompanies a peripheral stimulus. It would therefore seem to have a preemptive effect. Although the concept of preemptive analgesia generated much interest, no drugs have been definitively shown to have a preemptive effect in the human clinical situation. Given the compelling laboratory evidence of a preemptive effect in animal experiments, a further examination of ondansetron in this respect might be worthwhile.

In conclusion, this study suggests that the specific 5HT3 receptor antagonist ondansetron may have an analgesic effect in chronic benign neuropathic pain, and it seems likely that this effect is produced by an action on the neurones in the spinal cord that code and transmit peripheral nociceptive stimuli.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 16, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press