Suppression of pain behavior in nerve-injured rats by an anti-inflammatory drug: Promises and caveats for translation to clinical applications in man
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Antti Pertovaara
In this issue, Zanjani et al. [1] report that systemic administration of an anti-inflammatory drug, nimesulide, suppressed hypersensitivity in animals with a peripheral nerve injury. The nimesulide-induced antihypersensitivity effect was accompanied by a reduction in the serum concentration of a proinflammatory cytokine, interleukin-6. These results obtained in an experimental animal model of peripheral neuropathy add to abundant evidence indicating that the immune system plays an important role in pain hypersensitivity in various pathophysiological conditions [2].
With attempts to translate experimental animal results, such as those by Zanjani et al. [1], to human clinical practice, one needs to take into account a number of caveats as pointed out in several recent reviews [3,4,5,6,7,8]. While there appears to be a wide agreement that experimental animal models have proved valuable in extending our understanding of pathophysiological pain mechanisms, there are also limitations in the translation of rodent results on analgesic drugs to clinical practice in humans. A notable example is that rodent models of pain failed to predict clinical efficacy of neurokinin 1 antagonists [9]. On the other hand, with some drugs preclinical animal data has predicted analgesic efficacy in clinical patients [10,11].
There are several factors that may contribute to limitations in the translation of experimental animal studies to clinical studies. For example, most of the animal studies assessing analgesic efficacy of drugs are performed with young male rats, whereas human patients with chronic pain are most commonly middle-aged females [7]. Human brain imaging studies indicate that the cerebral cortical structures play an important role in the perception of pain, while pain in experimental animals is typically assessed using reflex responses that involve only subcortical circuitries [3]. In particular with cortical structures, species differences provide an additional challenge for the translation of results in rodents to humans [12]. While spontaneous pain is of great clinical importance, experimental animal studies usually focus on assessing evoked pain, due to difficulty in the assessment spontaneous pain in animals; although a hypersensitive response to a painful test stimulus is considered to reflect the magnitude of spontaneous pain, in some conditions it may dissociate from spontaneous pain, as everyone with an experience from a sunburn knows (hypersensitivity without on-going pain). Time interval between the lesion and testing period also provides a confounding factor, since human patients may have had chronic pain for several months or years, whereas efficacy of analgesic drugs in experimental animal studies is usually assessed a few days or weeks after induction of the pathophysiological condition. Concerning studies on peripheral neuropathy, it has been pointed out that while most of the experimental animal studies deal with peripheral nerve injury, in clinical conditions neuropathic pain is in most cases due to causes other than peripheral nerve injury [5]. Moreover, most of the animal studies attempt to determine the analgesic effects on the sensory-discriminative aspects of pain (such as pain threshold), whereas only few experimental animal studies attempt to assess the emotional component of pain, although the latter is associated with suffering that brings the patient to the doctor.
There are a number of suggestions to improve the predictive validity of experimental animal studies in bringing analgesic treatments to the clinic. Among them are the proposals to assess, in addition to reflex responses, also more complex outcome measures (e.g., cortically dependent operant escape tests) and emotional-like pain behavior (e.g., aversive place-conditioning) [3,7]. Moreover, animal models matching, as far as possible, clinical conditions, and testing animals with natural diseases might help in improving the translation of experimental results to the clinic [5,8]. Still, it may be argued that the approach used by e.g. Zanjani et al. [1] that includes peripheral nerve injury and reflex testing in experimental animals has its place in the arsenal as one of the first steps in the development of analgesic drugs against neuropathy. Since the mechanism underlying the reflex response in animals [13] as well as pain hypersensitivity in human patients [3] may vary depending on the submodality of test stimulation, it is an advantage to assess analgesic efficacy against different types of test stimuli, as Zanjani et al. did [1]. While their results promise that an anti-inflammatory drug is an effective mechanism-based treatment against some forms of neuropathic pain, one should still be cautious with translation of experimental animal results to the clinic, due to many caveats, as pointed out in the above cited reviews.
DOI of refers to article: 10.1016/j.sjpain.2010.08.003.
References
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© 2010 Scandinavian Association for the Study of Pain
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Artikel in diesem Heft
- Editorial comment
- Importance of clinical neurophysiological tests in the evaluation of pain: Indispensable in complex pain conditions
- Educational case report
- Difficult diagnosis of facial pain: A case report and mini-review
- Editorial comment
- Nerve block—A reliable diagnostic tool?
- Review
- Diagnostic blocks for chronic pain
- Editorial comment and review
- What do maltreatment and schemas have to do with the treatment of chronic pain?
- Clinical pain research
- Early maladaptive schemas in Finnish adult chronic male and female pain patients
- Editorial comment
- Electrically induced pain models: The benefit of “electric feel”
- Original experimental
- Cross-over evaluation of electrically induced pain and hyperalgesia
- Editorial comment
- Social work in a pain clinic
- Observational studies
- Patients referred from a multidisciplinary pain clinic to the social worker, their socio-demographic profile and the contribution of the social worker to the management of the patients
- Clinicial pain research
- Patients referred from a multidisciplinary pain clinic to the social worker, their general health, pain condition, treatment and outcome
- Editorial comment
- Suppression of pain behavior in nerve-injured rats by an anti-inflammatory drug: Promises and caveats for translation to clinical applications in man
- Original experimental
- The attenuation of pain behaviour and serum interleukin-6 concentration by nimesulide in a rat model of neuropathic pain
- Corrigendum
- Corrigendum to “A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of 7 day buprenorphine transdermal patch in osteoarthritis patients naïve to potent-opioids” [Scandinavian Journal of Pain 1 (2010) 122-141]
