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Do Animal Models Tell Us about Human Pain?
Supported by a grant from Endo Pharmaceuticals, Inc., USA
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain MedicineUSA
Advisory Board
Michael J. Cousins, MD, DSCPain Medicine, Palliative MedicineAustralia
Maria Adele Giamberardino, MD Internal Medicine, Physiology Italy
Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada
M.R. Rajagopal, MDPain Medicine, Palliative MedicineIndia
Maree T. Smith, PhD Pharmacology Australia
Claudia Sommer, MDNeurologyGermany
Harriët M. Wittink, PhD, PT Physical Therapy The Netherlands
Production
Elizabeth Endres, Associate Editor Kathleen E. Havers, Programs Coordinator Karen Smaalders, Marketing and Communications Manager
Pain remains an important health problem, with estimates of the cost of common pain conditions being many billions of dollars per year in developed countries.1 Although pain in some patients could be controlled by better application of exist-ing therapies, other conditions lack effective treatments. Although a major research effort continues to be devoted to resolve these problems, concerns have been ex-pressed at the relative lack of success in translating the ever-growing body of basic science data obtained using animal models into new, effective and safe clinical an-algesics.2–8 Significant successes have arisen from basic pain research, including the development of theories regarding pain mechanisms such as the gate control theory, the concept of neuroplasticity, and an understanding of the cellular and molecular mechanisms of peripheral and central sensitization. These developments in the un-derstanding of pain mechanisms based on experimental data have been translated into clinical practice, resulting in implementation of multimodal approaches to pain relief, earlier or preemptive provision of analgesia, and extended postoperative pain management.
Similarly, new drug delivery systems and approaches have been developed, largely based on preclinical research. Examples include patient-controlled analgesia (PCA); transdermal, transmucosal, topical, intranasal, and neuraxial (intrathecal/epidural) administration of opioid analgesics, local anesthetics, and nonsteroidal anti-inflam-matory drugs; and extended-release opioid and nonopioid analgesics. These advances have enabled clinicians to improve pain management and tailor pain therapy to the individual patient.
New work on the many signal-transduction pathways that contribute to peripheral and central sensitization has resulted in numerous attempts at new drug develop-ment targeting the nociceptive pathways at the transcriptional, translational, and posttranslational level. However, although there are currently many potential targets for new drug development—adenosine receptors, cannabinoid receptors (CB1, CB2), chemokines, cytokines, nerve growth factor, glutamate receptors, neurokinin receptors, NMDA receptors, potassium channels, purinergic P2 receptors, transient receptor potential channels, and voltage-gated calcium and sodium channels—the uneasy truth is that few truly new drugs have been brought into clinical practice as a direct result of this research activity. The drugs that have been introduced are either analgesics of the same class as others already in clinical use or have been de-rived from astute clinical observation in other settings (e.g., gabapentin, clonidine, lidocaine, and ketamine).
Vol. XVIII, Issue 5 July 2010
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Pain and GeneticsNeuropathic PainMusculoskeletal Pain
Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends independent verification of diagnoses and drug dosages.
For permission to reprint or translate this article, contact:
International Association for the Study of Pain • 111 Queen Anne Avenue North, Suite 501, Seattle, WA 98109-4955 USATel: +1-206-283-0311 • Fax: +1-206-283-9403 • Email: [email protected] • www.iasp-pain.org
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approach should be integrated into translational pain research, making it a multidimensional translation. Additionally, the evaluation of tissue from naturally occurring disease states may provide vital information in the translational jigsaw—informa-tion about the neurobiology of pain in the natural disease state. This tissue is available—peripheral tissue can be readily ob-tained from the millions of joint surgeries performed each year on pet dogs,68 and central nervous system tissues are available from the thousands of dogs with OA-associated pain that are euthanized each year. So far, the assumption has been that the mechanisms discovered in a rodent model are relevant to the natural disease state. An informative approach would be to ask: “What mechanisms are altered in the natural disease state?”
Conclusion
It is clear that significant advances have been made in under-standing pain and pain mechanisms using current in vivo mod-els, but in virtually no instances have these advances translated into new drugs for pain control in the clinic. Of course, this fail-ure may result from flaws at one or more stages of the process—technical or conceptual flaws in the basic preclinical research, the clinical study design, the selection of the clinical population for study, or the way clinical studies are run.2 Regardless, it makes sense to optimize the approach to gathering basic scientif-ic information on pain, and to make this information as relevant as possible to the target population. A closer rapport between clinicians and basic researchers is needed. Additionally, the cur-rent unidimensional translational model could be expanded to embrace other opportunities such as naturally occurring disease, thus creating a multidimensional translational approach to the development of analgesics for human pain control.
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43. Siegel SM, Lee JW, Oaklander AL. Needlestick distal nerve injury in rats models symptoms of complex regional pain syndrome. Anesth Analg 2007;105:1820–9.
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45. Westlund KN, Vera-Portocarrero LP, Zhang L, Wei J, Quast MJ, Cleeland CS. fMRIofsupraspinalareasaftermorphineandoneweekpancreaticinflammationin rats. Neuroimage 2009;44:23–34.
46. Vera-Portocarrero LP, Lu Y, Westlund KN. Nociception in persistent pancrea-titis in rats: effects of morphine and neuropeptide alterations. Anesthesiology 2003;98:474–84.
47. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996;64:493–501.
48. Gonzalez MI, Field MJ, Bramwell S, McCleary S, Singh L. Ovariohysterectomy in the rat: a model of surgical pain for evaluation of pre-emptive analgesia? Pain 2000;88:79–88.
49. Lascelles BD, Cripps PJ, Jones A, Waterman AE. Post-operative central hyper-sensitivity and pain: the pre-emptive value of pethidine for ovariohysterectomy. Pain 1997;73:461–71.
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51. Bove SE, Laemont KD, Brooker RM, Osborn MN, Sanchez BM, Guzman RE, Hook KE, Juneau PL, Connor JR, Kilgore KS. Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and second-ary hyperalgesia. Osteoarthritis Cartilage 2006;14:1041–8.
52. McDougall JJ, Andruski B, Schuelert N, Hallgrimsson B, Matyas JR. Unravelling the relationship between age, nociception and joint destruction in naturally occur-ring osteoarthritis of Dunkin Hartley guinea pigs. Pain 2009;141:222–32.
53. Clements DN, Carter SD, Innes JF, Ollier WE. Genetic basis of secondary os-teoarthritis in dogs with joint dysplasia. Am J Vet Res 2006;67:909–18.
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55. Clements DN, Carter SD, Innes JF, Ollier WE, Day PJ. Analysis of normal and osteoarthritic canine cartilage mRNA expression by quantitative polymerase chain reaction. Arthritis Res Ther 2006;8:R158.
56. BudsbergSC,JohnstonSA,SchwarzPD,DeCampCE,ClaxtonR.Efficacyofetodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999;214:206–10.
57. HoltsingerRH,ParkerRB,BealeBS,FriedmanRL.Thetherapeuticefficacyofcarprofen (Rimadyl-V) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Traumatol 1992;5:140–4.
58. Vasseur PB, Johnson AL, Budsberg SC, Lincoln JD, Toombs JP, Whitehair JG, LentzEL.Randomized,controlledtrialoftheefficacyofcarprofen,anonsteroidalanti-inflammatorydrug,inthetreatmentofosteoarthritisindogs.JAmVetMedAssoc 1995;206:807–11.
59. Lascelles BD, Freire M, Roe SC, DePuy V, Smith E, Marcellin-Little DJ. Evalu-ation of functional outcome after BFX total hip replacement using a pressure sensitive walkway. Vet Surg 2010;39:71–7.
60. Lascelles BD, Henry JB, Brown J, et al. Cross-sectional study evaluating the prevalence of radiographic degenerative joint disease in domesticated cats. Vet Surg; in press.
61. Brown DC, Boston RC, Coyne JC, Farrar JT. Development and psychometric testing of an instrument designed to measure chronic pain in dogs with osteoar-thritis. Am J Vet Res 2007;68:631–7.
62. Brown DC, Boston RC, Coyne JC, Farrar JT. Ability of the canine brief pain in-ventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc 2008;233:1278–83.
63. Hielm-Bjorkman AK, Rita H, Tulamo RM. Psychometric testing of the Helsinki chronic pain index by completion of a questionnaire in Finnish by owners of dogs with chronic signs of pain caused by osteoarthritis. Am J Vet Res 2009;70:727–34.
64. Hansen BD, Lascelles BD, Keene BW, Adams AK, Thomson AE. Evaluation of an accelerometer for at-home monitoring of spontaneous activity in dogs. Am J Vet Res 2007;68:468–75.
65. Lascelles BD, Hansen BD, Thomson A, Pierce CC, Boland E, Smith ES. Evalu-ation of a digitally integrated accelerometer-based activity monitor for the mea-surement of activity in cats. Vet Anaesth Analg 2008;35:173–83.
66. Voss K, Imhof J, Kaestner S, Montavon PM. Force plate gait analysis at the walk and trot in dogs with low-grade hindlimb lameness. Vet Comp Orthop Traumatol 2007;20:299–304.
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B. Duncan X. Lascelles, BSc, BVSC, PhD
Comparative Pain Research Laboratory & Integrated Pain Management Service
North Carolina State University College of Veterinary Medicine
Raleigh, North Carolina 27606, USA
Email: [email protected]
Prof. Paul A. Flecknell, VetMB, PhD
Comparative Biology Centre, Medical School, University of Newcastle
Newcastle upon Tyne, NE2 4HH, United Kingdom
3
relationship between spontaneous pain and hypersensitivity or allodynia is only just being elucidated for common conditions such as osteoarthritis in humans.19 Rodent models involving reflex tests and measures of hypersensitivity and allodynia may well provide useful information, but just as the patient popu-lation and outcome measures need to be carefully defined in clinical trials, there also needs to be careful appraisal of what the rodent models (the chosen assay and outcome measures) actually represent.
Timing of Lesion and of Testing Periods in Rodent Models
Very often, the time a lesion or stimulus has been present in the rodent model is very much shorter than the human condition. For example, pain measures are taken up to 28 days following iodoacetate injection in one rat model of osteoarthritis (OA),20 but human patients presenting with OA pain have often had the painful disease for many years. Even accounting for the relevant lifespan differences, this difference in chronicity may well have significant implications for the neurobiology of pain in the two scenarios.
Although there are currently many potential targets for new drug
development … the uneasy truth is that few truly new drugs have been brought into clinical practice as a
direct result of this research activity
Subject Choices
There are differences between individual humans and between males and females in pain and response to analgesics.21,22 Ad-ditionally, there are significant effects of race and ethnicity on clinical and experimental pain.23–25 Nevertheless, most basic pain studies use young adult, male Sprague Dawley rats. This choice would be acceptable if the results could be predict-ably translated to the human population. However, in terms of chronic pain, middle-aged female patients are predominantly affected.26 The potential confounding effect of sex bias in basic studies was highlighted by Mogil and Chanda,27 who found that between 1996 and 2005, almost 80% of studies published in PAIN used male subjects only, with only 4% collecting and discussing data from both sexes. This bias has been suggested to be partly responsible for the negative effects of three large clinical trials evaluating the opioid analgesia enhancing effects of dextromethorphan.28 Prior to 2002, all the relevant basic studies of the interactions of various NMDA antagonists and opioids had used male rodents. Overall, these studies showed an enhancement of opioid analgesia by dextromethorphan. The inference was that such an approach would be useful clinically in humans. Subsequently, basic research work that included female rodents showed there was a significant sex effect on
mu-opioid/NMDA-receptor interactions.29,30 Had this effect been known before the human clinical trials were launched, a different approach may have been taken in the trials.
If a putative analgesic has been tested in an evoked pain model, it might not nec-essarily translate to relief of continuous
spontaneous pain in clinical patients
Other Factors Affecting Pain Studies in Animals
Factors such as diet, type of restraint, bedding, temperature, ambient noise, distractions, handling, odors, housing condi-tions, and social interactions and communication can all affect the results of pain studies.31,32 Often, full details of the experi-mental conditions are not reported in basic science studies, and so the impact of these factors cannot be assessed. Additionally, rodent studies rarely use blinding or randomization, and rarely are all the rodents used accounted for. These factors can lead to bias, just as they can in clinical studies, and they can inappro-priately influence what clinical studies are performed.
What Can Be Done?
Given the general consensus of a lack of predictability of animal models of pain,2–8 it is important to consider what can be done to improve their predictive validity in bringing novel treatments to the clinic.
Refine Experimental Protocol and Reporting
An improvement in experimental methodology and reporting of animal model data is needed.3,5 A more complete description of the methodology with respect to selection of animals, hus-bandry, experimental conditions, and accounting for outcomes of all animals in the experiment(s) should be uniformly report-ed. Additionally, blinding and randomization in basic science studies will help to remove bias. Statistical power should be considered, and the choice of subject (sex, strain, age) should be considered in the discussion of the implications of the re-sults. Use of factorial study designs would enable the potential relevance of the results to be increased, such as by inclusion of both sexes and more than one strain, without requiring the use of increased numbers of animals.33
Include More Complex Outcome Measures
Consideration should be given to the inclusion of a broad pack-age of outcome measures to try to capture the multifaceted nature of pain and pain relief. By necessity, this procedure is going to be more complicated and take longer to perform. However, if “processing efficiency” in basic studies (such as those screening analgesics using reflex responses) is sacrificed for a more clinically relevant result, the extra time involved will be worthwhile.4
4
The assessment of clinical pain in humans presents a unique problem compared to other major health conditions, such as heart disease or cancer, which can be detected by objective bio-logical measurements. The assessment of pain relies on subjec-tive reports from patients, but the same subjective self-reports cannot readily be obtained from laboratory animals. Overcom-ing this fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require development of measures of animal pain that enable the affective dimension of pain to be assessed. The discussion becomes even more complex with the sugges-tion that humans have certain neuroanatomical features that are crucial for pain sensation34—features that are not present in some of the species most commonly used in pain research, such as rodents.
Overcoming the fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require
development of measures of animal pain that enable the affective
dimension of pain to be assessed
More complex models can be developed, and although none of these models directly measure the affective component of pain, they potentially provide better markers of more complex processing of nociceptive information.35 For example, resolv-ing conflicts between positive and negative reinforcement can be exploited in operant assays of analgesics,6 and self-adminis-tration paradigms have been used as measures of pain that may require a degree of awareness of the stimulus and an apprecia-tion of the change in state produced by analgesic consump-tion.36 Additionally, conditioned place preference/conditioned place aversion strategies can be used.37,38 When operant and reflexive measures have been compared, the operant measures appear to provide the most clinically relevant result.6 Greater validity and relevance of rodent models may be achieved by the measurement of spontaneous pain behaviors. This measure poses problems for researchers as rodents are prey animals and are particularly good at hiding pain behaviors. Additionally, researchers need to avoid the trap of deciding for themselves what behaviors are relevant to measure—or else the assay be-comes a test of their preconceived ideas about what behaviors are relevant. Thus complex, detailed ethograms of normal and pain-related behavior need to be developed. Just as photocell and video-tracking systems have enabled automation of oper-ant measures, increasingly sophisticated video-based behavior-al algorithms are being assessed for their utility in quantifying spontaneously emitted behaviors and in developing ethograms of animals in their home cages over extended periods of time.39
Improve/Introduce More Models of Disease
If many current models lack face validity, one approach would be to introduce models that have greater fidelity with the natu-rally occurring painful disease being targeted. Recently, as outlined by Mogil,4 rodent models have been developed that attempt to more directly model prevalent clinical pain syn-dromes, often by inducing the disease state itself. Examples include bone cancer pain,40 labor pain,41 burn pain,42 complex regional pain syndrome,43 HIV-induced painful neuropathy,44 pancreatitis pain,45,46 postoperative pain,47–49 sprain pain,50 and surgically induced osteoarthritis pain.51
A potentially very useful and relevant approach to the development of analgesic
compounds would be to consider using animals with a naturally
occurring disease that is similar to the human condition
A potentially very useful and relevant approach to the devel-opment of analgesic compounds would be to consider using animals with a naturally occurring disease that is similar to the human condition. Certain species used for in vivo studies are particularly susceptible to naturally occurring painful disease, including the Dunkin-Hartley guinea-pig.52 Many nonrodent animals develop the same diseases as humans. For example, it is known that certain breeds of dogs are susceptible to OA—in-deed, it is one of the most common diseases of pet dogs, with up to 30% of all dogs having the condition. OA of the hip in the dog usually occurs as a result of hip dysplasia53,54 and is considered to be similar to secondary OA in humans.55 The need for models of OA to have both features of joint pathology and pain has recent-ly been highlighted,20 and the canine spontaneous disease model fits these criteria.56–59 Similarly, racehorses are treated for painful musculoskeletal conditions, and recent work has highlighted the very high prevalence of degenerative joint disease in cats.60 These types of spontaneous conditions could expand the scope of preclinical assessment of novel pain therapies. However, such collaboration with veterinary medicine was noticeably absent from a recent review of the challenges and future directions for translational pain research.8 Studies in companion animals are feasible, and randomized, blinded “clinical trials” with sample sizes approaching those of some human clinical trials are pos-sible. Additionally, validated subjective measures61–63 and objec-tive measures such as accelerometry64,65 and force plate or pres-sure mat techniques58,59,66,67 are available.
It is possible to study drug effects in animals with diseases that are much closer models of the human clinical condition than many traditional laboratory-based in vivo models. This
2
The terms “translational medicine” and “translational pain research” generally refer to bench or basic research in rodents, which is attempted to be translated directly into changes in clinical practice. This work could be called “unidimensional” translational research. In this respect, there have been several notable failures in pain research. Neurokinin (NK1) receptor research promised much, but NK1 receptor antagonists have not been associated with clinical utility.9 Other examples are selective Na channel blockers and glycine site NMDA an-tagonists, compounds that according to extensive and detailed preclinical work in rodent models were expected to be highly efficacious, and yet the results were very disappointing.10,11 There are few examples of analgesic drugs that have been suc-cessfully translated from “bench to bedside” based on animal models alone with no clinical precedent of analgesic effects in humans. The conopeptide, ziconotide, maybe the only ex-ample, but even with this example of successful translation of research, the clinical utility of the drug is limited.
Developments in the understanding of pain mechanisms based on experimental data have been
translated into clinical practice
What Is Wrong with the Models?
Given the need for improvements in the spectrum of tools avail-able to clinicians for treating pain, and the very significant cost to the health industry of drugs and treatments that fail at the human clinical trial stage, it is important to evaluate why the cur-rent models and approaches to using them have been less than optimal. This problem has been comprehensively covered in re-cent reviews,4–8 and the salient points are outlined here.
Lack of Face Validity or Fidelity
The current animal models of pain appear to have worked well for mechanistic studies, but poorly as a basis for selecting new analgesic candidates.4 Although these mechanistic studies are often hailed as significant advances, they may have led to a focus on mechanisms that lack relevancy to clinical pain. This problem could have arisen through the use of inappropriate models or models that lack face validity or fidelity to the hu-man condition being targeted. Face validity refers to whether or not the model appears, at face value, to be measuring or reflecting what it is supposed to measure. These concerns are similar to the discussions on face validity of a subjective as-sessment instrument for pain—if the instrument asked ques-tions about aspects that did not appear to be associated with or affected by pain, one might question the face validity of the instrument. A good example of lack of face validity has been outlined by Rice,5 who points out that peripheral nerve injury (e.g., nerve ligation) models have become the industry standard for the preclinical assessment of novel analgesics targeted at
neuropathic pain, and yet the majority of randomized clinical trials of putative analgesics for neuropathic pain have been in patients without traumatic peripheral nerve injury. Similarly, one can ask whether the acetic acid writhing tests,12–14 or the orofacial injection of formalin,15 or the intra-articular injection of Freud’s complete adjuvant (FCA)16 actually mirror any clini-cal conditions. Such models of pain do give us pieces of the puzzle, but perhaps assuming that the results from such studies can be translated directly into human studies is rather naive.
Another problem with the current rodent models is that they are self-fulfilling as preclinical work progresses. That is, a model, such as the FCA model, might be used to unravel the mecha-nisms of “pain,” and once the mechanisms have been elucidated, a candidate analgesic is chosen based on the mechanisms unrav-eled.17 It is to be expected that the candidate analgesic would be effective when tested in the model, but whether or not this work is relevant to a clinical condition will depend on whether or not the clinical condition shares the same neurobiological mecha-nisms. Additionally, many rodent models use the “pre-injury” administration of candidate analgesics, which, in clinical pain conditions, often is not how the compounds could be used. Obvi-ously it is not possible to exactly and consistently reproduce hu-man clinical pain conditions in laboratory animals, and various models that lack face validity or fidelity with the target clinical condition do have an important role to play in pain research. However, their limitations, especially for direct unidirectional translation to human clinical trials, should be acknowledged.
Lack of Involvement of the Cerebral Cortex and Reliance on Reflex Tests or Innate Behaviors and Measures of Hypersensitivity
Vierck 6 makes the argument that because human imaging stud-ies show that the cerebral cortical structures participate in the conscious perception of pain, it is imperative that assessments of pain in laboratory animals quantify behavioral responses to sensory experiences that are cortically medicated. Reflex tests, such as tail flick and paw withdrawal, may not involve cortical structures. Even jumping (such as on a hotplate) can be consid-ered to be a bulbospinal reflex, and many measured behaviors such as vocalization, scratching, biting, licking, and guarding are behaviors that can be seen in decerebrate animals.18 Ad-ditionally, many of the tests that are used to evaluate candi-date analgesics are based on evoked withdrawal responses. These tests most likely do not measure pain itself, but rather the hyperactive reflexes that are thought to accompany pain. Evoked pain is a problem for a significant number of people with chronic pain, but continuous spontaneous pain, which oc-curs independent of any particular activity, is of much greater prevalence. Thus, if a putative analgesic has been tested in an evoked pain model, it might not necessarily translate to relief of continuous spontaneous pain in clinical patients because the molecule would need to be active under different neurobio-logical conditions to treat pain in this different scenario. The
3
relationship between spontaneous pain and hypersensitivity or allodynia is only just being elucidated for common conditions such as osteoarthritis in humans.19 Rodent models involving reflex tests and measures of hypersensitivity and allodynia may well provide useful information, but just as the patient popu-lation and outcome measures need to be carefully defined in clinical trials, there also needs to be careful appraisal of what the rodent models (the chosen assay and outcome measures) actually represent.
Timing of Lesion and of Testing Periods in Rodent Models
Very often, the time a lesion or stimulus has been present in the rodent model is very much shorter than the human condition. For example, pain measures are taken up to 28 days following iodoacetate injection in one rat model of osteoarthritis (OA),20 but human patients presenting with OA pain have often had the painful disease for many years. Even accounting for the relevant lifespan differences, this difference in chronicity may well have significant implications for the neurobiology of pain in the two scenarios.
Although there are currently many potential targets for new drug
development … the uneasy truth is that few truly new drugs have been brought into clinical practice as a
direct result of this research activity
Subject Choices
There are differences between individual humans and between males and females in pain and response to analgesics.21,22 Ad-ditionally, there are significant effects of race and ethnicity on clinical and experimental pain.23–25 Nevertheless, most basic pain studies use young adult, male Sprague Dawley rats. This choice would be acceptable if the results could be predict-ably translated to the human population. However, in terms of chronic pain, middle-aged female patients are predominantly affected.26 The potential confounding effect of sex bias in basic studies was highlighted by Mogil and Chanda,27 who found that between 1996 and 2005, almost 80% of studies published in PAIN used male subjects only, with only 4% collecting and discussing data from both sexes. This bias has been suggested to be partly responsible for the negative effects of three large clinical trials evaluating the opioid analgesia enhancing effects of dextromethorphan.28 Prior to 2002, all the relevant basic studies of the interactions of various NMDA antagonists and opioids had used male rodents. Overall, these studies showed an enhancement of opioid analgesia by dextromethorphan. The inference was that such an approach would be useful clinically in humans. Subsequently, basic research work that included female rodents showed there was a significant sex effect on
mu-opioid/NMDA-receptor interactions.29,30 Had this effect been known before the human clinical trials were launched, a different approach may have been taken in the trials.
If a putative analgesic has been tested in an evoked pain model, it might not nec-essarily translate to relief of continuous
spontaneous pain in clinical patients
Other Factors Affecting Pain Studies in Animals
Factors such as diet, type of restraint, bedding, temperature, ambient noise, distractions, handling, odors, housing condi-tions, and social interactions and communication can all affect the results of pain studies.31,32 Often, full details of the experi-mental conditions are not reported in basic science studies, and so the impact of these factors cannot be assessed. Additionally, rodent studies rarely use blinding or randomization, and rarely are all the rodents used accounted for. These factors can lead to bias, just as they can in clinical studies, and they can inappro-priately influence what clinical studies are performed.
What Can Be Done?
Given the general consensus of a lack of predictability of animal models of pain,2–8 it is important to consider what can be done to improve their predictive validity in bringing novel treatments to the clinic.
Refine Experimental Protocol and Reporting
An improvement in experimental methodology and reporting of animal model data is needed.3,5 A more complete description of the methodology with respect to selection of animals, hus-bandry, experimental conditions, and accounting for outcomes of all animals in the experiment(s) should be uniformly report-ed. Additionally, blinding and randomization in basic science studies will help to remove bias. Statistical power should be considered, and the choice of subject (sex, strain, age) should be considered in the discussion of the implications of the re-sults. Use of factorial study designs would enable the potential relevance of the results to be increased, such as by inclusion of both sexes and more than one strain, without requiring the use of increased numbers of animals.33
Include More Complex Outcome Measures
Consideration should be given to the inclusion of a broad pack-age of outcome measures to try to capture the multifaceted nature of pain and pain relief. By necessity, this procedure is going to be more complicated and take longer to perform. However, if “processing efficiency” in basic studies (such as those screening analgesics using reflex responses) is sacrificed for a more clinically relevant result, the extra time involved will be worthwhile.4
4
The assessment of clinical pain in humans presents a unique problem compared to other major health conditions, such as heart disease or cancer, which can be detected by objective bio-logical measurements. The assessment of pain relies on subjec-tive reports from patients, but the same subjective self-reports cannot readily be obtained from laboratory animals. Overcom-ing this fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require development of measures of animal pain that enable the affective dimension of pain to be assessed. The discussion becomes even more complex with the sugges-tion that humans have certain neuroanatomical features that are crucial for pain sensation34—features that are not present in some of the species most commonly used in pain research, such as rodents.
Overcoming the fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require
development of measures of animal pain that enable the affective
dimension of pain to be assessed
More complex models can be developed, and although none of these models directly measure the affective component of pain, they potentially provide better markers of more complex processing of nociceptive information.35 For example, resolv-ing conflicts between positive and negative reinforcement can be exploited in operant assays of analgesics,6 and self-adminis-tration paradigms have been used as measures of pain that may require a degree of awareness of the stimulus and an apprecia-tion of the change in state produced by analgesic consump-tion.36 Additionally, conditioned place preference/conditioned place aversion strategies can be used.37,38 When operant and reflexive measures have been compared, the operant measures appear to provide the most clinically relevant result.6 Greater validity and relevance of rodent models may be achieved by the measurement of spontaneous pain behaviors. This measure poses problems for researchers as rodents are prey animals and are particularly good at hiding pain behaviors. Additionally, researchers need to avoid the trap of deciding for themselves what behaviors are relevant to measure—or else the assay be-comes a test of their preconceived ideas about what behaviors are relevant. Thus complex, detailed ethograms of normal and pain-related behavior need to be developed. Just as photocell and video-tracking systems have enabled automation of oper-ant measures, increasingly sophisticated video-based behavior-al algorithms are being assessed for their utility in quantifying spontaneously emitted behaviors and in developing ethograms of animals in their home cages over extended periods of time.39
Improve/Introduce More Models of Disease
If many current models lack face validity, one approach would be to introduce models that have greater fidelity with the natu-rally occurring painful disease being targeted. Recently, as outlined by Mogil,4 rodent models have been developed that attempt to more directly model prevalent clinical pain syn-dromes, often by inducing the disease state itself. Examples include bone cancer pain,40 labor pain,41 burn pain,42 complex regional pain syndrome,43 HIV-induced painful neuropathy,44 pancreatitis pain,45,46 postoperative pain,47–49 sprain pain,50 and surgically induced osteoarthritis pain.51
A potentially very useful and relevant approach to the development of analgesic
compounds would be to consider using animals with a naturally
occurring disease that is similar to the human condition
A potentially very useful and relevant approach to the devel-opment of analgesic compounds would be to consider using animals with a naturally occurring disease that is similar to the human condition. Certain species used for in vivo studies are particularly susceptible to naturally occurring painful disease, including the Dunkin-Hartley guinea-pig.52 Many nonrodent animals develop the same diseases as humans. For example, it is known that certain breeds of dogs are susceptible to OA—in-deed, it is one of the most common diseases of pet dogs, with up to 30% of all dogs having the condition. OA of the hip in the dog usually occurs as a result of hip dysplasia53,54 and is considered to be similar to secondary OA in humans.55 The need for models of OA to have both features of joint pathology and pain has recent-ly been highlighted,20 and the canine spontaneous disease model fits these criteria.56–59 Similarly, racehorses are treated for painful musculoskeletal conditions, and recent work has highlighted the very high prevalence of degenerative joint disease in cats.60 These types of spontaneous conditions could expand the scope of preclinical assessment of novel pain therapies. However, such collaboration with veterinary medicine was noticeably absent from a recent review of the challenges and future directions for translational pain research.8 Studies in companion animals are feasible, and randomized, blinded “clinical trials” with sample sizes approaching those of some human clinical trials are pos-sible. Additionally, validated subjective measures61–63 and objec-tive measures such as accelerometry64,65 and force plate or pres-sure mat techniques58,59,66,67 are available.
It is possible to study drug effects in animals with diseases that are much closer models of the human clinical condition than many traditional laboratory-based in vivo models. This
2
The terms “translational medicine” and “translational pain research” generally refer to bench or basic research in rodents, which is attempted to be translated directly into changes in clinical practice. This work could be called “unidimensional” translational research. In this respect, there have been several notable failures in pain research. Neurokinin (NK1) receptor research promised much, but NK1 receptor antagonists have not been associated with clinical utility.9 Other examples are selective Na channel blockers and glycine site NMDA an-tagonists, compounds that according to extensive and detailed preclinical work in rodent models were expected to be highly efficacious, and yet the results were very disappointing.10,11 There are few examples of analgesic drugs that have been suc-cessfully translated from “bench to bedside” based on animal models alone with no clinical precedent of analgesic effects in humans. The conopeptide, ziconotide, maybe the only ex-ample, but even with this example of successful translation of research, the clinical utility of the drug is limited.
Developments in the understanding of pain mechanisms based on experimental data have been
translated into clinical practice
What Is Wrong with the Models?
Given the need for improvements in the spectrum of tools avail-able to clinicians for treating pain, and the very significant cost to the health industry of drugs and treatments that fail at the human clinical trial stage, it is important to evaluate why the cur-rent models and approaches to using them have been less than optimal. This problem has been comprehensively covered in re-cent reviews,4–8 and the salient points are outlined here.
Lack of Face Validity or Fidelity
The current animal models of pain appear to have worked well for mechanistic studies, but poorly as a basis for selecting new analgesic candidates.4 Although these mechanistic studies are often hailed as significant advances, they may have led to a focus on mechanisms that lack relevancy to clinical pain. This problem could have arisen through the use of inappropriate models or models that lack face validity or fidelity to the hu-man condition being targeted. Face validity refers to whether or not the model appears, at face value, to be measuring or reflecting what it is supposed to measure. These concerns are similar to the discussions on face validity of a subjective as-sessment instrument for pain—if the instrument asked ques-tions about aspects that did not appear to be associated with or affected by pain, one might question the face validity of the instrument. A good example of lack of face validity has been outlined by Rice,5 who points out that peripheral nerve injury (e.g., nerve ligation) models have become the industry standard for the preclinical assessment of novel analgesics targeted at
neuropathic pain, and yet the majority of randomized clinical trials of putative analgesics for neuropathic pain have been in patients without traumatic peripheral nerve injury. Similarly, one can ask whether the acetic acid writhing tests,12–14 or the orofacial injection of formalin,15 or the intra-articular injection of Freud’s complete adjuvant (FCA)16 actually mirror any clini-cal conditions. Such models of pain do give us pieces of the puzzle, but perhaps assuming that the results from such studies can be translated directly into human studies is rather naive.
Another problem with the current rodent models is that they are self-fulfilling as preclinical work progresses. That is, a model, such as the FCA model, might be used to unravel the mecha-nisms of “pain,” and once the mechanisms have been elucidated, a candidate analgesic is chosen based on the mechanisms unrav-eled.17 It is to be expected that the candidate analgesic would be effective when tested in the model, but whether or not this work is relevant to a clinical condition will depend on whether or not the clinical condition shares the same neurobiological mecha-nisms. Additionally, many rodent models use the “pre-injury” administration of candidate analgesics, which, in clinical pain conditions, often is not how the compounds could be used. Obvi-ously it is not possible to exactly and consistently reproduce hu-man clinical pain conditions in laboratory animals, and various models that lack face validity or fidelity with the target clinical condition do have an important role to play in pain research. However, their limitations, especially for direct unidirectional translation to human clinical trials, should be acknowledged.
Lack of Involvement of the Cerebral Cortex and Reliance on Reflex Tests or Innate Behaviors and Measures of Hypersensitivity
Vierck 6 makes the argument that because human imaging stud-ies show that the cerebral cortical structures participate in the conscious perception of pain, it is imperative that assessments of pain in laboratory animals quantify behavioral responses to sensory experiences that are cortically medicated. Reflex tests, such as tail flick and paw withdrawal, may not involve cortical structures. Even jumping (such as on a hotplate) can be consid-ered to be a bulbospinal reflex, and many measured behaviors such as vocalization, scratching, biting, licking, and guarding are behaviors that can be seen in decerebrate animals.18 Ad-ditionally, many of the tests that are used to evaluate candi-date analgesics are based on evoked withdrawal responses. These tests most likely do not measure pain itself, but rather the hyperactive reflexes that are thought to accompany pain. Evoked pain is a problem for a significant number of people with chronic pain, but continuous spontaneous pain, which oc-curs independent of any particular activity, is of much greater prevalence. Thus, if a putative analgesic has been tested in an evoked pain model, it might not necessarily translate to relief of continuous spontaneous pain in clinical patients because the molecule would need to be active under different neurobio-logical conditions to treat pain in this different scenario. The
3
relationship between spontaneous pain and hypersensitivity or allodynia is only just being elucidated for common conditions such as osteoarthritis in humans.19 Rodent models involving reflex tests and measures of hypersensitivity and allodynia may well provide useful information, but just as the patient popu-lation and outcome measures need to be carefully defined in clinical trials, there also needs to be careful appraisal of what the rodent models (the chosen assay and outcome measures) actually represent.
Timing of Lesion and of Testing Periods in Rodent Models
Very often, the time a lesion or stimulus has been present in the rodent model is very much shorter than the human condition. For example, pain measures are taken up to 28 days following iodoacetate injection in one rat model of osteoarthritis (OA),20 but human patients presenting with OA pain have often had the painful disease for many years. Even accounting for the relevant lifespan differences, this difference in chronicity may well have significant implications for the neurobiology of pain in the two scenarios.
Although there are currently many potential targets for new drug
development … the uneasy truth is that few truly new drugs have been brought into clinical practice as a
direct result of this research activity
Subject Choices
There are differences between individual humans and between males and females in pain and response to analgesics.21,22 Ad-ditionally, there are significant effects of race and ethnicity on clinical and experimental pain.23–25 Nevertheless, most basic pain studies use young adult, male Sprague Dawley rats. This choice would be acceptable if the results could be predict-ably translated to the human population. However, in terms of chronic pain, middle-aged female patients are predominantly affected.26 The potential confounding effect of sex bias in basic studies was highlighted by Mogil and Chanda,27 who found that between 1996 and 2005, almost 80% of studies published in PAIN used male subjects only, with only 4% collecting and discussing data from both sexes. This bias has been suggested to be partly responsible for the negative effects of three large clinical trials evaluating the opioid analgesia enhancing effects of dextromethorphan.28 Prior to 2002, all the relevant basic studies of the interactions of various NMDA antagonists and opioids had used male rodents. Overall, these studies showed an enhancement of opioid analgesia by dextromethorphan. The inference was that such an approach would be useful clinically in humans. Subsequently, basic research work that included female rodents showed there was a significant sex effect on
mu-opioid/NMDA-receptor interactions.29,30 Had this effect been known before the human clinical trials were launched, a different approach may have been taken in the trials.
If a putative analgesic has been tested in an evoked pain model, it might not nec-essarily translate to relief of continuous
spontaneous pain in clinical patients
Other Factors Affecting Pain Studies in Animals
Factors such as diet, type of restraint, bedding, temperature, ambient noise, distractions, handling, odors, housing condi-tions, and social interactions and communication can all affect the results of pain studies.31,32 Often, full details of the experi-mental conditions are not reported in basic science studies, and so the impact of these factors cannot be assessed. Additionally, rodent studies rarely use blinding or randomization, and rarely are all the rodents used accounted for. These factors can lead to bias, just as they can in clinical studies, and they can inappro-priately influence what clinical studies are performed.
What Can Be Done?
Given the general consensus of a lack of predictability of animal models of pain,2–8 it is important to consider what can be done to improve their predictive validity in bringing novel treatments to the clinic.
Refine Experimental Protocol and Reporting
An improvement in experimental methodology and reporting of animal model data is needed.3,5 A more complete description of the methodology with respect to selection of animals, hus-bandry, experimental conditions, and accounting for outcomes of all animals in the experiment(s) should be uniformly report-ed. Additionally, blinding and randomization in basic science studies will help to remove bias. Statistical power should be considered, and the choice of subject (sex, strain, age) should be considered in the discussion of the implications of the re-sults. Use of factorial study designs would enable the potential relevance of the results to be increased, such as by inclusion of both sexes and more than one strain, without requiring the use of increased numbers of animals.33
Include More Complex Outcome Measures
Consideration should be given to the inclusion of a broad pack-age of outcome measures to try to capture the multifaceted nature of pain and pain relief. By necessity, this procedure is going to be more complicated and take longer to perform. However, if “processing efficiency” in basic studies (such as those screening analgesics using reflex responses) is sacrificed for a more clinically relevant result, the extra time involved will be worthwhile.4
4
The assessment of clinical pain in humans presents a unique problem compared to other major health conditions, such as heart disease or cancer, which can be detected by objective bio-logical measurements. The assessment of pain relies on subjec-tive reports from patients, but the same subjective self-reports cannot readily be obtained from laboratory animals. Overcom-ing this fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require development of measures of animal pain that enable the affective dimension of pain to be assessed. The discussion becomes even more complex with the sugges-tion that humans have certain neuroanatomical features that are crucial for pain sensation34—features that are not present in some of the species most commonly used in pain research, such as rodents.
Overcoming the fundamental mismatch between the approach to pain evaluation in human clinical patients and the approach used in pain research may require
development of measures of animal pain that enable the affective
dimension of pain to be assessed
More complex models can be developed, and although none of these models directly measure the affective component of pain, they potentially provide better markers of more complex processing of nociceptive information.35 For example, resolv-ing conflicts between positive and negative reinforcement can be exploited in operant assays of analgesics,6 and self-adminis-tration paradigms have been used as measures of pain that may require a degree of awareness of the stimulus and an apprecia-tion of the change in state produced by analgesic consump-tion.36 Additionally, conditioned place preference/conditioned place aversion strategies can be used.37,38 When operant and reflexive measures have been compared, the operant measures appear to provide the most clinically relevant result.6 Greater validity and relevance of rodent models may be achieved by the measurement of spontaneous pain behaviors. This measure poses problems for researchers as rodents are prey animals and are particularly good at hiding pain behaviors. Additionally, researchers need to avoid the trap of deciding for themselves what behaviors are relevant to measure—or else the assay be-comes a test of their preconceived ideas about what behaviors are relevant. Thus complex, detailed ethograms of normal and pain-related behavior need to be developed. Just as photocell and video-tracking systems have enabled automation of oper-ant measures, increasingly sophisticated video-based behavior-al algorithms are being assessed for their utility in quantifying spontaneously emitted behaviors and in developing ethograms of animals in their home cages over extended periods of time.39
Improve/Introduce More Models of Disease
If many current models lack face validity, one approach would be to introduce models that have greater fidelity with the natu-rally occurring painful disease being targeted. Recently, as outlined by Mogil,4 rodent models have been developed that attempt to more directly model prevalent clinical pain syn-dromes, often by inducing the disease state itself. Examples include bone cancer pain,40 labor pain,41 burn pain,42 complex regional pain syndrome,43 HIV-induced painful neuropathy,44 pancreatitis pain,45,46 postoperative pain,47–49 sprain pain,50 and surgically induced osteoarthritis pain.51
A potentially very useful and relevant approach to the development of analgesic
compounds would be to consider using animals with a naturally
occurring disease that is similar to the human condition
A potentially very useful and relevant approach to the devel-opment of analgesic compounds would be to consider using animals with a naturally occurring disease that is similar to the human condition. Certain species used for in vivo studies are particularly susceptible to naturally occurring painful disease, including the Dunkin-Hartley guinea-pig.52 Many nonrodent animals develop the same diseases as humans. For example, it is known that certain breeds of dogs are susceptible to OA—in-deed, it is one of the most common diseases of pet dogs, with up to 30% of all dogs having the condition. OA of the hip in the dog usually occurs as a result of hip dysplasia53,54 and is considered to be similar to secondary OA in humans.55 The need for models of OA to have both features of joint pathology and pain has recent-ly been highlighted,20 and the canine spontaneous disease model fits these criteria.56–59 Similarly, racehorses are treated for painful musculoskeletal conditions, and recent work has highlighted the very high prevalence of degenerative joint disease in cats.60 These types of spontaneous conditions could expand the scope of preclinical assessment of novel pain therapies. However, such collaboration with veterinary medicine was noticeably absent from a recent review of the challenges and future directions for translational pain research.8 Studies in companion animals are feasible, and randomized, blinded “clinical trials” with sample sizes approaching those of some human clinical trials are pos-sible. Additionally, validated subjective measures61–63 and objec-tive measures such as accelerometry64,65 and force plate or pres-sure mat techniques58,59,66,67 are available.
It is possible to study drug effects in animals with diseases that are much closer models of the human clinical condition than many traditional laboratory-based in vivo models. This
2
The terms “translational medicine” and “translational pain research” generally refer to bench or basic research in rodents, which is attempted to be translated directly into changes in clinical practice. This work could be called “unidimensional” translational research. In this respect, there have been several notable failures in pain research. Neurokinin (NK1) receptor research promised much, but NK1 receptor antagonists have not been associated with clinical utility.9 Other examples are selective Na channel blockers and glycine site NMDA an-tagonists, compounds that according to extensive and detailed preclinical work in rodent models were expected to be highly efficacious, and yet the results were very disappointing.10,11 There are few examples of analgesic drugs that have been suc-cessfully translated from “bench to bedside” based on animal models alone with no clinical precedent of analgesic effects in humans. The conopeptide, ziconotide, maybe the only ex-ample, but even with this example of successful translation of research, the clinical utility of the drug is limited.
Developments in the understanding of pain mechanisms based on experimental data have been
translated into clinical practice
What Is Wrong with the Models?
Given the need for improvements in the spectrum of tools avail-able to clinicians for treating pain, and the very significant cost to the health industry of drugs and treatments that fail at the human clinical trial stage, it is important to evaluate why the cur-rent models and approaches to using them have been less than optimal. This problem has been comprehensively covered in re-cent reviews,4–8 and the salient points are outlined here.
Lack of Face Validity or Fidelity
The current animal models of pain appear to have worked well for mechanistic studies, but poorly as a basis for selecting new analgesic candidates.4 Although these mechanistic studies are often hailed as significant advances, they may have led to a focus on mechanisms that lack relevancy to clinical pain. This problem could have arisen through the use of inappropriate models or models that lack face validity or fidelity to the hu-man condition being targeted. Face validity refers to whether or not the model appears, at face value, to be measuring or reflecting what it is supposed to measure. These concerns are similar to the discussions on face validity of a subjective as-sessment instrument for pain—if the instrument asked ques-tions about aspects that did not appear to be associated with or affected by pain, one might question the face validity of the instrument. A good example of lack of face validity has been outlined by Rice,5 who points out that peripheral nerve injury (e.g., nerve ligation) models have become the industry standard for the preclinical assessment of novel analgesics targeted at
neuropathic pain, and yet the majority of randomized clinical trials of putative analgesics for neuropathic pain have been in patients without traumatic peripheral nerve injury. Similarly, one can ask whether the acetic acid writhing tests,12–14 or the orofacial injection of formalin,15 or the intra-articular injection of Freud’s complete adjuvant (FCA)16 actually mirror any clini-cal conditions. Such models of pain do give us pieces of the puzzle, but perhaps assuming that the results from such studies can be translated directly into human studies is rather naive.
Another problem with the current rodent models is that they are self-fulfilling as preclinical work progresses. That is, a model, such as the FCA model, might be used to unravel the mecha-nisms of “pain,” and once the mechanisms have been elucidated, a candidate analgesic is chosen based on the mechanisms unrav-eled.17 It is to be expected that the candidate analgesic would be effective when tested in the model, but whether or not this work is relevant to a clinical condition will depend on whether or not the clinical condition shares the same neurobiological mecha-nisms. Additionally, many rodent models use the “pre-injury” administration of candidate analgesics, which, in clinical pain conditions, often is not how the compounds could be used. Obvi-ously it is not possible to exactly and consistently reproduce hu-man clinical pain conditions in laboratory animals, and various models that lack face validity or fidelity with the target clinical condition do have an important role to play in pain research. However, their limitations, especially for direct unidirectional translation to human clinical trials, should be acknowledged.
Lack of Involvement of the Cerebral Cortex and Reliance on Reflex Tests or Innate Behaviors and Measures of Hypersensitivity
Vierck 6 makes the argument that because human imaging stud-ies show that the cerebral cortical structures participate in the conscious perception of pain, it is imperative that assessments of pain in laboratory animals quantify behavioral responses to sensory experiences that are cortically medicated. Reflex tests, such as tail flick and paw withdrawal, may not involve cortical structures. Even jumping (such as on a hotplate) can be consid-ered to be a bulbospinal reflex, and many measured behaviors such as vocalization, scratching, biting, licking, and guarding are behaviors that can be seen in decerebrate animals.18 Ad-ditionally, many of the tests that are used to evaluate candi-date analgesics are based on evoked withdrawal responses. These tests most likely do not measure pain itself, but rather the hyperactive reflexes that are thought to accompany pain. Evoked pain is a problem for a significant number of people with chronic pain, but continuous spontaneous pain, which oc-curs independent of any particular activity, is of much greater prevalence. Thus, if a putative analgesic has been tested in an evoked pain model, it might not necessarily translate to relief of continuous spontaneous pain in clinical patients because the molecule would need to be active under different neurobio-logical conditions to treat pain in this different scenario. The
Do Animal Models Tell Us about Human Pain?
Supported by a grant from Endo Pharmaceuticals, Inc., USA
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain MedicineUSA
Advisory Board
Michael J. Cousins, MD, DSCPain Medicine, Palliative MedicineAustralia
Maria Adele Giamberardino, MD Internal Medicine, Physiology Italy
Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada
M.R. Rajagopal, MDPain Medicine, Palliative MedicineIndia
Maree T. Smith, PhD Pharmacology Australia
Claudia Sommer, MDNeurologyGermany
Harriët M. Wittink, PhD, PT Physical Therapy The Netherlands
Production
Elizabeth Endres, Associate Editor Kathleen E. Havers, Programs Coordinator Karen Smaalders, Marketing and Communications Manager
Pain remains an important health problem, with estimates of the cost of common pain conditions being many billions of dollars per year in developed countries.1 Although pain in some patients could be controlled by better application of exist-ing therapies, other conditions lack effective treatments. Although a major research effort continues to be devoted to resolve these problems, concerns have been ex-pressed at the relative lack of success in translating the ever-growing body of basic science data obtained using animal models into new, effective and safe clinical an-algesics.2–8 Significant successes have arisen from basic pain research, including the development of theories regarding pain mechanisms such as the gate control theory, the concept of neuroplasticity, and an understanding of the cellular and molecular mechanisms of peripheral and central sensitization. These developments in the un-derstanding of pain mechanisms based on experimental data have been translated into clinical practice, resulting in implementation of multimodal approaches to pain relief, earlier or preemptive provision of analgesia, and extended postoperative pain management.
Similarly, new drug delivery systems and approaches have been developed, largely based on preclinical research. Examples include patient-controlled analgesia (PCA); transdermal, transmucosal, topical, intranasal, and neuraxial (intrathecal/epidural) administration of opioid analgesics, local anesthetics, and nonsteroidal anti-inflam-matory drugs; and extended-release opioid and nonopioid analgesics. These advances have enabled clinicians to improve pain management and tailor pain therapy to the individual patient.
New work on the many signal-transduction pathways that contribute to peripheral and central sensitization has resulted in numerous attempts at new drug develop-ment targeting the nociceptive pathways at the transcriptional, translational, and posttranslational level. However, although there are currently many potential targets for new drug development—adenosine receptors, cannabinoid receptors (CB1, CB2), chemokines, cytokines, nerve growth factor, glutamate receptors, neurokinin receptors, NMDA receptors, potassium channels, purinergic P2 receptors, transient receptor potential channels, and voltage-gated calcium and sodium channels—the uneasy truth is that few truly new drugs have been brought into clinical practice as a direct result of this research activity. The drugs that have been introduced are either analgesics of the same class as others already in clinical use or have been de-rived from astute clinical observation in other settings (e.g., gabapentin, clonidine, lidocaine, and ketamine).
Vol. XVIII, Issue 5 July 2010
Upcoming Issues
®
Pain and GeneticsNeuropathic PainMusculoskeletal Pain
Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends independent verification of diagnoses and drug dosages.
For permission to reprint or translate this article, contact:
International Association for the Study of Pain • 111 Queen Anne Avenue North, Suite 501, Seattle, WA 98109-4955 USATel: +1-206-283-0311 • Fax: +1-206-283-9403 • Email: [email protected] • www.iasp-pain.org
Copyright © 2010. All rights reserved. ISSN 1083-0707.
Printed in the U.S.A. 5
References
1. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 2003;290:2443–54.
2. Quessy SN. Two-stage enriched enrolment pain trials: a brief review of designs and opportunities for broader application. Pain 2010;148:8–13.
3. QuessySN.Commenton:Animalmodelsandthepredictionofefficacyinclinicaltrials of analgesic drugs: A critical appraisal and a call for uniform reporting stan-dards. Pain 2009;142:284–5.
4. Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci 2009;10:283–94.
5. Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I; Preclinical Pain Consortium, Mogil JS, Stöhr T. Animal models and the predictionofefficacyinclinicaltrialsofanalgesicdrugs:acriticalappraisalandcall for uniform reporting standards. Pain 2008;139:243–7.
6. Vierck CJ, Hansson PT, Yezierski RP. Clinical and pre-clinical pain assessment: are we measuring the same thing? Pain 2008;135:7–10.
7. Craig AD. A rat is not a monkey is not a human: comment on Mogil. Nat Rev Neurosci 2009;10:466.
8. Mao J. Translational pain research: achievements and challenges. J Pain 2009;10:1001–11.
9. Hill R. NK1 (substance P) receptor antagonists: why are they not analgesic in humans? Trends Pharmacol Sci 2000;21:244–6.
10. Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain 2002;3:227–33.
11. Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002;59:1694–700.
12. Khalifa MM, Abdelbaky NA. Synthesis of new imidazolyl acetic acid derivatives withanti-inflammatoryandanalgesicactivities.ArchPharmRes2008;31:419–23.
13. Park SH, Sim YB, Choi SM, Seo YJ, Kwon MS, Lee JK, Suh HW. Antinociceptive profilesandmechanismsoforallyadministeredvanillininthemice.ArchPharmRes 2009;32:1643–9.
14. Seo YJ, Kwon MS, Park SH, Sim YB, Choi SM, Huh GH, Lee JK, Suh HW. The analgesic effect of decursinol. Arch Pharm Res 2009;32:937–43.
15. Munoz J, Navarro C, Noriega V, Pinardi G, Sierralta F, Prieto JC, Miranda HF. SynergismbetweenCOX-3inhibitorsintwoanimalmodelsofpain.Inflammop-harmacology 2010;18:65–71.
16. Lam FF, Ng ES. Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexamethasone in rats. Br J Pharmacol 2010;159:958–69.
17. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR. JNK-induced MCP-1 production in spinal cord astrocytes contrib-utes to central sensitization and neuropathic pain. J Neurosci 2009;29:4096–108.
18. Matthies BK, Franklin KB. Formalin pain is expressed in decerebrate rats but not attenuated by morphine. Pain 1992;51:199–206.
19. Imamura M, Imamura ST, Kaziyama HH, RA, Hsing WT, de Souza LP, Cutait MM, Fregni F, Camanho GL. Impact of nervous system hyperalgesia on pain, dis-ability, and quality of life in patients with knee osteoarthritis: a controlled analysis. Arthritis Rheum 2008;59:1424–31.
20. Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, Kidd B, Bevan S, Winter J. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004;112:83–93.
21. Hechler T, Chalkiadis GA, Hasan C, Kosfelder J, Meyerhoff U, Vocks S, Zernikow B. Sex differences in pain intensity in adolescents suffering from cancer: differ-ences in pain memories? J Pain 2009;10:586–93.
22. Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain perception and treatment. Pain Med 2009;10:289–99.
23. Wang H, Papoiu AD, Coghill RC, Patel T, Wang N, Yosipovitch G. Ethnic differ-ences in pain, itch and thermal detection in response to topical capsaicin: African Americansdisplayanotablylimitedhyperalgesiaandneurogenicinflammation.Br J Dermatol 2010;162:1023–9.
24. Allen KD, Helmick CG, Schwartz TA, DeVellis RF, Renner JB, Jordan JM. Racial differences in self-reported pain and function among individuals with radiographic hip and knee osteoarthritis: the Johnston County Osteoarthritis Project. Osteoar-thritis Cartilage 2009;17:1132–6.
25. Komiyama O, Wang K, Svensson P, Arendt-Nielsen L, Kawara M, De Laat A. Ethnicdifferencesregardingsensory,pain,andreflexresponsesinthetrigeminalregion. Clin Neurophysiol 2009;120:384–9.
26. Berkley KJ. Sex differences in pain. Behav Brain Sci 1997;20:371–80; discussion 435–513.
27. Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic sci-ence studies of pain. Pain 2005;117:1–5.
28. Galer BS, Lee D, Ma T, Nagle B, Schlagheck TG. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demon-strate enhanced opioid analgesia or reduction in tolerance. Pain 2005;115:284–95.
29. GriselJE,AllenS,NemmaniKV,FeeJR,CarlissR.Theinfluenceofdex-tromethorphanonmorphineanalgesiainSwissWebstermiceissex-specific.Pharmacol Biochem Behav 2005;81:131–8.
30. Craft RM, Lee DA. NMDA antagonist modulation of morphine antinociception in female vs. male rats. Pharmacol Biochem Behav 2005;80:639–49.
31. Robinson I, Dowdall T, Meert TF. Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats. Neurosci Lett 2004;368:107–11.
32. Langford DJ, Crager SE, Shehzad Z, Smith SB, Sotocinal SG, Levenstadt JS, Chanda ML, Levitin DJ, Mogil JS. Social modulation of pain as evidence for em-pathy in mice. Science 2006;312:1967–70.
33. Festing MF. Principles: the need for better experimental design. Trends Pharma-col Sci 2003;24:341–5.
34. CraigAD,BushnellMC,ZhangET,BlomqvistA.Athalamicnucleusspecificforpain and temperature sensation. Nature 1994;372:770–3.
35. National Research Council. Recognition and alleviation of pain in laboratory animals. Washington, DC: National Research Council; 2009.
36. Martin TJ, Kim SA, Buechler NL, Porreca F, Eisenach JC. Opioid self-administra-tion in the nerve-injured rat: relevance of antiallodynic effects to drug consump-tion and effects of intrathecal analgesics. Anesthesiology 2007;106:312–22.
approach should be integrated into translational pain research, making it a multidimensional translation. Additionally, the evaluation of tissue from naturally occurring disease states may provide vital information in the translational jigsaw—informa-tion about the neurobiology of pain in the natural disease state. This tissue is available—peripheral tissue can be readily ob-tained from the millions of joint surgeries performed each year on pet dogs,68 and central nervous system tissues are available from the thousands of dogs with OA-associated pain that are euthanized each year. So far, the assumption has been that the mechanisms discovered in a rodent model are relevant to the natural disease state. An informative approach would be to ask: “What mechanisms are altered in the natural disease state?”
Conclusion
It is clear that significant advances have been made in under-standing pain and pain mechanisms using current in vivo mod-els, but in virtually no instances have these advances translated into new drugs for pain control in the clinic. Of course, this fail-ure may result from flaws at one or more stages of the process—technical or conceptual flaws in the basic preclinical research, the clinical study design, the selection of the clinical population for study, or the way clinical studies are run.2 Regardless, it makes sense to optimize the approach to gathering basic scientif-ic information on pain, and to make this information as relevant as possible to the target population. A closer rapport between clinicians and basic researchers is needed. Additionally, the cur-rent unidimensional translational model could be expanded to embrace other opportunities such as naturally occurring disease, thus creating a multidimensional translational approach to the development of analgesics for human pain control.
37. Sufka KJ. Conditioned place preference paradigm: a novel approach for analge-sic drug assessment against chronic pain. Pain 1994;58:355–66.
38. King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F. Unmasking the tonic-aversive state in neuropathic pain. Nat Neu-rosci 2009;12:1364–6.
39. Roughan JV, Wright-Williams SL, Flecknell PA. Automated analysis of postop-erative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice. Lab Anim 2009;43:17–26.
40. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mechanisms of cancer pain. Nat Rev Cancer 2002;2:201–9.
41. Tong C, Conklin DR, Liu B, Ririe DG, Eisenach JC. Assessment of behav-ior during labor in rats and effect of intrathecal morphine. Anesthesiology 2008;108:1081–6.
42. Nozaki-Taguchi N, Yaksh TL. A novel model of primary and secondary hyperalge-sia after mild thermal injury in the rat. Neurosci Lett 1998;254:25–8.
43. Siegel SM, Lee JW, Oaklander AL. Needlestick distal nerve injury in rats models symptoms of complex regional pain syndrome. Anesth Analg 2007;105:1820–9.
44. Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice AS. Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain. Brain 2007;130:2688–702.
45. Westlund KN, Vera-Portocarrero LP, Zhang L, Wei J, Quast MJ, Cleeland CS. fMRIofsupraspinalareasaftermorphineandoneweekpancreaticinflammationin rats. Neuroimage 2009;44:23–34.
46. Vera-Portocarrero LP, Lu Y, Westlund KN. Nociception in persistent pancrea-titis in rats: effects of morphine and neuropeptide alterations. Anesthesiology 2003;98:474–84.
47. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996;64:493–501.
48. Gonzalez MI, Field MJ, Bramwell S, McCleary S, Singh L. Ovariohysterectomy in the rat: a model of surgical pain for evaluation of pre-emptive analgesia? Pain 2000;88:79–88.
49. Lascelles BD, Cripps PJ, Jones A, Waterman AE. Post-operative central hyper-sensitivity and pain: the pre-emptive value of pethidine for ovariohysterectomy. Pain 1997;73:461–71.
50. Koo ST, Park YI, Lim KS, Chung K, Chung JM. Acupuncture analgesia in a new rat model of ankle sprain pain. Pain 2002;99:423–31.
51. Bove SE, Laemont KD, Brooker RM, Osborn MN, Sanchez BM, Guzman RE, Hook KE, Juneau PL, Connor JR, Kilgore KS. Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and second-ary hyperalgesia. Osteoarthritis Cartilage 2006;14:1041–8.
52. McDougall JJ, Andruski B, Schuelert N, Hallgrimsson B, Matyas JR. Unravelling the relationship between age, nociception and joint destruction in naturally occur-ring osteoarthritis of Dunkin Hartley guinea pigs. Pain 2009;141:222–32.
53. Clements DN, Carter SD, Innes JF, Ollier WE. Genetic basis of secondary os-teoarthritis in dogs with joint dysplasia. Am J Vet Res 2006;67:909–18.
54. Hays L, Zhang Z, Mateescu RG, Lust G, Burton-Wurster NI, Todhunter RJ. Quantitative genetics of secondary hip joint osteoarthritis in a Labrador Retriever-Greyhound pedigree. Am J Vet Res 2007;68:35–41.
55. Clements DN, Carter SD, Innes JF, Ollier WE, Day PJ. Analysis of normal and osteoarthritic canine cartilage mRNA expression by quantitative polymerase chain reaction. Arthritis Res Ther 2006;8:R158.
56. BudsbergSC,JohnstonSA,SchwarzPD,DeCampCE,ClaxtonR.Efficacyofetodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999;214:206–10.
57. HoltsingerRH,ParkerRB,BealeBS,FriedmanRL.Thetherapeuticefficacyofcarprofen (Rimadyl-V) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Traumatol 1992;5:140–4.
58. Vasseur PB, Johnson AL, Budsberg SC, Lincoln JD, Toombs JP, Whitehair JG, LentzEL.Randomized,controlledtrialoftheefficacyofcarprofen,anonsteroidalanti-inflammatorydrug,inthetreatmentofosteoarthritisindogs.JAmVetMedAssoc 1995;206:807–11.
59. Lascelles BD, Freire M, Roe SC, DePuy V, Smith E, Marcellin-Little DJ. Evalu-ation of functional outcome after BFX total hip replacement using a pressure sensitive walkway. Vet Surg 2010;39:71–7.
60. Lascelles BD, Henry JB, Brown J, et al. Cross-sectional study evaluating the prevalence of radiographic degenerative joint disease in domesticated cats. Vet Surg; in press.
61. Brown DC, Boston RC, Coyne JC, Farrar JT. Development and psychometric testing of an instrument designed to measure chronic pain in dogs with osteoar-thritis. Am J Vet Res 2007;68:631–7.
62. Brown DC, Boston RC, Coyne JC, Farrar JT. Ability of the canine brief pain in-ventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc 2008;233:1278–83.
63. Hielm-Bjorkman AK, Rita H, Tulamo RM. Psychometric testing of the Helsinki chronic pain index by completion of a questionnaire in Finnish by owners of dogs with chronic signs of pain caused by osteoarthritis. Am J Vet Res 2009;70:727–34.
64. Hansen BD, Lascelles BD, Keene BW, Adams AK, Thomson AE. Evaluation of an accelerometer for at-home monitoring of spontaneous activity in dogs. Am J Vet Res 2007;68:468–75.
65. Lascelles BD, Hansen BD, Thomson A, Pierce CC, Boland E, Smith ES. Evalu-ation of a digitally integrated accelerometer-based activity monitor for the mea-surement of activity in cats. Vet Anaesth Analg 2008;35:173–83.
66. Voss K, Imhof J, Kaestner S, Montavon PM. Force plate gait analysis at the walk and trot in dogs with low-grade hindlimb lameness. Vet Comp Orthop Traumatol 2007;20:299–304.
67. Lascelles BD, Roe SC, Smith E, Reynolds L, Markham J, Marcellin-Little D, Bergh MS, Budsberg SC. Evaluation of a pressure walkway system for measure-ment of vertical limb forces in clinically normal dogs. Am J Vet Res 2006;67:277–82.
68. Lascelles BD, King S, Roe S, Marcellin-Little DJ, Jones S. Expression and activ-ity of COX-1 and 2 and 5-LOX in joint tissues from dogs with naturally occurring coxofemoral joint osteoarthritis. J Orthop Res 2009;27:1204–8.
B. Duncan X. Lascelles, BSc, BVSC, PhD
Comparative Pain Research Laboratory & Integrated Pain Management Service
North Carolina State University College of Veterinary Medicine
Raleigh, North Carolina 27606, USA
Email: [email protected]
Prof. Paul A. Flecknell, VetMB, PhD
Comparative Biology Centre, Medical School, University of Newcastle
Newcastle upon Tyne, NE2 4HH, United Kingdom
Do Animal Models Tell Us about Human Pain?
Supported by a grant from Endo Pharmaceuticals, Inc., USA
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA Anesthesiology, Pain MedicineUSA
Advisory Board
Michael J. Cousins, MD, DSCPain Medicine, Palliative MedicineAustralia
Maria Adele Giamberardino, MD Internal Medicine, Physiology Italy
Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada
M.R. Rajagopal, MDPain Medicine, Palliative MedicineIndia
Maree T. Smith, PhD Pharmacology Australia
Claudia Sommer, MDNeurologyGermany
Harriët M. Wittink, PhD, PT Physical Therapy The Netherlands
Production
Elizabeth Endres, Associate Editor Kathleen E. Havers, Programs Coordinator Karen Smaalders, Marketing and Communications Manager
Pain remains an important health problem, with estimates of the cost of common pain conditions being many billions of dollars per year in developed countries.1 Although pain in some patients could be controlled by better application of exist-ing therapies, other conditions lack effective treatments. Although a major research effort continues to be devoted to resolve these problems, concerns have been ex-pressed at the relative lack of success in translating the ever-growing body of basic science data obtained using animal models into new, effective and safe clinical an-algesics.2–8 Significant successes have arisen from basic pain research, including the development of theories regarding pain mechanisms such as the gate control theory, the concept of neuroplasticity, and an understanding of the cellular and molecular mechanisms of peripheral and central sensitization. These developments in the un-derstanding of pain mechanisms based on experimental data have been translated into clinical practice, resulting in implementation of multimodal approaches to pain relief, earlier or preemptive provision of analgesia, and extended postoperative pain management.
Similarly, new drug delivery systems and approaches have been developed, largely based on preclinical research. Examples include patient-controlled analgesia (PCA); transdermal, transmucosal, topical, intranasal, and neuraxial (intrathecal/epidural) administration of opioid analgesics, local anesthetics, and nonsteroidal anti-inflam-matory drugs; and extended-release opioid and nonopioid analgesics. These advances have enabled clinicians to improve pain management and tailor pain therapy to the individual patient.
New work on the many signal-transduction pathways that contribute to peripheral and central sensitization has resulted in numerous attempts at new drug develop-ment targeting the nociceptive pathways at the transcriptional, translational, and posttranslational level. However, although there are currently many potential targets for new drug development—adenosine receptors, cannabinoid receptors (CB1, CB2), chemokines, cytokines, nerve growth factor, glutamate receptors, neurokinin receptors, NMDA receptors, potassium channels, purinergic P2 receptors, transient receptor potential channels, and voltage-gated calcium and sodium channels—the uneasy truth is that few truly new drugs have been brought into clinical practice as a direct result of this research activity. The drugs that have been introduced are either analgesics of the same class as others already in clinical use or have been de-rived from astute clinical observation in other settings (e.g., gabapentin, clonidine, lidocaine, and ketamine).
Vol. XVIII, Issue 5 July 2010
Upcoming Issues
®
Pain and GeneticsNeuropathic PainMusculoskeletal Pain
Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends independent verification of diagnoses and drug dosages.
For permission to reprint or translate this article, contact:
International Association for the Study of Pain • 111 Queen Anne Avenue North, Suite 501, Seattle, WA 98109-4955 USATel: +1-206-283-0311 • Fax: +1-206-283-9403 • Email: [email protected] • www.iasp-pain.org
Copyright © 2010. All rights reserved. ISSN 1083-0707.
Printed in the U.S.A. 5
References
1. Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 2003;290:2443–54.
2. Quessy SN. Two-stage enriched enrolment pain trials: a brief review of designs and opportunities for broader application. Pain 2010;148:8–13.
3. QuessySN.Commenton:Animalmodelsandthepredictionofefficacyinclinicaltrials of analgesic drugs: A critical appraisal and a call for uniform reporting stan-dards. Pain 2009;142:284–5.
4. Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci 2009;10:283–94.
5. Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I; Preclinical Pain Consortium, Mogil JS, Stöhr T. Animal models and the predictionofefficacyinclinicaltrialsofanalgesicdrugs:acriticalappraisalandcall for uniform reporting standards. Pain 2008;139:243–7.
6. Vierck CJ, Hansson PT, Yezierski RP. Clinical and pre-clinical pain assessment: are we measuring the same thing? Pain 2008;135:7–10.
7. Craig AD. A rat is not a monkey is not a human: comment on Mogil. Nat Rev Neurosci 2009;10:466.
8. Mao J. Translational pain research: achievements and challenges. J Pain 2009;10:1001–11.
9. Hill R. NK1 (substance P) receptor antagonists: why are they not analgesic in humans? Trends Pharmacol Sci 2000;21:244–6.
10. Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain 2002;3:227–33.
11. Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002;59:1694–700.
12. Khalifa MM, Abdelbaky NA. Synthesis of new imidazolyl acetic acid derivatives withanti-inflammatoryandanalgesicactivities.ArchPharmRes2008;31:419–23.
13. Park SH, Sim YB, Choi SM, Seo YJ, Kwon MS, Lee JK, Suh HW. Antinociceptive profilesandmechanismsoforallyadministeredvanillininthemice.ArchPharmRes 2009;32:1643–9.
14. Seo YJ, Kwon MS, Park SH, Sim YB, Choi SM, Huh GH, Lee JK, Suh HW. The analgesic effect of decursinol. Arch Pharm Res 2009;32:937–43.
15. Munoz J, Navarro C, Noriega V, Pinardi G, Sierralta F, Prieto JC, Miranda HF. SynergismbetweenCOX-3inhibitorsintwoanimalmodelsofpain.Inflammop-harmacology 2010;18:65–71.
16. Lam FF, Ng ES. Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexamethasone in rats. Br J Pharmacol 2010;159:958–69.
17. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR. JNK-induced MCP-1 production in spinal cord astrocytes contrib-utes to central sensitization and neuropathic pain. J Neurosci 2009;29:4096–108.
18. Matthies BK, Franklin KB. Formalin pain is expressed in decerebrate rats but not attenuated by morphine. Pain 1992;51:199–206.
19. Imamura M, Imamura ST, Kaziyama HH, RA, Hsing WT, de Souza LP, Cutait MM, Fregni F, Camanho GL. Impact of nervous system hyperalgesia on pain, dis-ability, and quality of life in patients with knee osteoarthritis: a controlled analysis. Arthritis Rheum 2008;59:1424–31.
20. Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, Kidd B, Bevan S, Winter J. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004;112:83–93.
21. Hechler T, Chalkiadis GA, Hasan C, Kosfelder J, Meyerhoff U, Vocks S, Zernikow B. Sex differences in pain intensity in adolescents suffering from cancer: differ-ences in pain memories? J Pain 2009;10:586–93.
22. Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain perception and treatment. Pain Med 2009;10:289–99.
23. Wang H, Papoiu AD, Coghill RC, Patel T, Wang N, Yosipovitch G. Ethnic differ-ences in pain, itch and thermal detection in response to topical capsaicin: African Americansdisplayanotablylimitedhyperalgesiaandneurogenicinflammation.Br J Dermatol 2010;162:1023–9.
24. Allen KD, Helmick CG, Schwartz TA, DeVellis RF, Renner JB, Jordan JM. Racial differences in self-reported pain and function among individuals with radiographic hip and knee osteoarthritis: the Johnston County Osteoarthritis Project. Osteoar-thritis Cartilage 2009;17:1132–6.
25. Komiyama O, Wang K, Svensson P, Arendt-Nielsen L, Kawara M, De Laat A. Ethnicdifferencesregardingsensory,pain,andreflexresponsesinthetrigeminalregion. Clin Neurophysiol 2009;120:384–9.
26. Berkley KJ. Sex differences in pain. Behav Brain Sci 1997;20:371–80; discussion 435–513.
27. Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic sci-ence studies of pain. Pain 2005;117:1–5.
28. Galer BS, Lee D, Ma T, Nagle B, Schlagheck TG. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demon-strate enhanced opioid analgesia or reduction in tolerance. Pain 2005;115:284–95.
29. GriselJE,AllenS,NemmaniKV,FeeJR,CarlissR.Theinfluenceofdex-tromethorphanonmorphineanalgesiainSwissWebstermiceissex-specific.Pharmacol Biochem Behav 2005;81:131–8.
30. Craft RM, Lee DA. NMDA antagonist modulation of morphine antinociception in female vs. male rats. Pharmacol Biochem Behav 2005;80:639–49.
31. Robinson I, Dowdall T, Meert TF. Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats. Neurosci Lett 2004;368:107–11.
32. Langford DJ, Crager SE, Shehzad Z, Smith SB, Sotocinal SG, Levenstadt JS, Chanda ML, Levitin DJ, Mogil JS. Social modulation of pain as evidence for em-pathy in mice. Science 2006;312:1967–70.
33. Festing MF. Principles: the need for better experimental design. Trends Pharma-col Sci 2003;24:341–5.
34. CraigAD,BushnellMC,ZhangET,BlomqvistA.Athalamicnucleusspecificforpain and temperature sensation. Nature 1994;372:770–3.
35. National Research Council. Recognition and alleviation of pain in laboratory animals. Washington, DC: National Research Council; 2009.
36. Martin TJ, Kim SA, Buechler NL, Porreca F, Eisenach JC. Opioid self-administra-tion in the nerve-injured rat: relevance of antiallodynic effects to drug consump-tion and effects of intrathecal analgesics. Anesthesiology 2007;106:312–22.
approach should be integrated into translational pain research, making it a multidimensional translation. Additionally, the evaluation of tissue from naturally occurring disease states may provide vital information in the translational jigsaw—informa-tion about the neurobiology of pain in the natural disease state. This tissue is available—peripheral tissue can be readily ob-tained from the millions of joint surgeries performed each year on pet dogs,68 and central nervous system tissues are available from the thousands of dogs with OA-associated pain that are euthanized each year. So far, the assumption has been that the mechanisms discovered in a rodent model are relevant to the natural disease state. An informative approach would be to ask: “What mechanisms are altered in the natural disease state?”
Conclusion
It is clear that significant advances have been made in under-standing pain and pain mechanisms using current in vivo mod-els, but in virtually no instances have these advances translated into new drugs for pain control in the clinic. Of course, this fail-ure may result from flaws at one or more stages of the process—technical or conceptual flaws in the basic preclinical research, the clinical study design, the selection of the clinical population for study, or the way clinical studies are run.2 Regardless, it makes sense to optimize the approach to gathering basic scientif-ic information on pain, and to make this information as relevant as possible to the target population. A closer rapport between clinicians and basic researchers is needed. Additionally, the cur-rent unidimensional translational model could be expanded to embrace other opportunities such as naturally occurring disease, thus creating a multidimensional translational approach to the development of analgesics for human pain control.
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B. Duncan X. Lascelles, BSc, BVSC, PhD
Comparative Pain Research Laboratory & Integrated Pain Management Service
North Carolina State University College of Veterinary Medicine
Raleigh, North Carolina 27606, USA
Email: [email protected]
Prof. Paul A. Flecknell, VetMB, PhD
Comparative Biology Centre, Medical School, University of Newcastle
Newcastle upon Tyne, NE2 4HH, United Kingdom