Ò
PAIN 155 (2014) 208–209
www.elsevier.com/locate/pain
Bridging the gaps: Special commentary
Can we stop pain before it starts? The prevention of chronic pain has been a goal for decades, and the present study uses pregabalin to gauge its ability to prevent persistent pain after nerve injury [9]. This is a nice article that uses behaviour and immunohistochemistry to probe the effects of the drug. It failed—so should we just give up, or are there issues with this study that need to be addressed in future investigations? The authors did observe that an early treatment worked better than a delayed one, supporting the idea that treating as soon as possible has some benefits. The drug was able to suppress cold and mechanical hypersensitivity during administration, but the abnormal responsivity produced by the nerve injury rapidly returned once the drug was turned off. Few experimental studies have attempted to try to prevent persistent pain with gabapentinoids, so the present study has great value. One facet is that the pregabalin was given spinally, and although this is a major site of action of the drug, the authors failed to see a change in the target protein, the alpha-2 delta subunit. Thus it may be that systemic routes, apart from mimicking the human use of the drug, could better target the dorsal root ganglion (DRG), allowing effects on translocation to occur. This is almost what one might expect because the consequences of the peripheral origins and the subsequent central changes leading to hypersensitivity caused by the neuropathy will re-emerge as the drug wears off. Thus, there is no disease modification, only control of the symptoms. There is a fascinating finding in the present study because the animals could be rendered analgesic during exposure to pregabalin without any change in certain markers of microglial activation. This suggests some caution in attribution of pain to nonneuronal systems. However, is it always the case that the pain of nerve injury cannot be prevented beyond the pharmacological actions of the drug? Last year De Felice et al. [4], in this journal, showed that rats that could produce a sustained intrinsic noradrenergic drive were protected from the behavioural consequences of nerve injury despite a persistence of certain neuropathic markers in the DRG. However, albeit given for shorter periods, gabapentin [5] and indeed morphine, although able to normalize behavioural and neuronal changes in a model of cancer-induced bone pain, lost their effects when the drug wore off, presumably reflecting a continued peripheral drive that re-establishes the pain state. Thus no prevention of the chronic pain state appears to occur unless the modulatory system is continually activated, through either drugs or endogenous signalling. In accordance with the negative findings in the detailed experimental setup [9], the corresponding clinical studies have so far also been negative regarding potential benefits of gabapentinoids to reduce persistent postsurgical pain. Although there may be
q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.10.024
general agreement that gabapentinoids may be valuable for reduction of early postoperative pain and opioid consumption [8], the optimal dose and duration of treatment in relation to different procedures and compared to side effects still require further studies. When it comes to the potential benefits of perioperative gabapentinoids on persistent postsurgical pain, 3 major reviews have been published during the last year based on 11 to 16 randomized controlled trials [2,3,8]. It becomes clear that there is a discrepancy between the positive findings of early perioperative gabapentinoids on acute postoperative pain, because the overall data do not support any positive effects on persistent postsurgical pain. However, as stated in the reviews [2,3,8], this conclusion is based on data that unfortunately come from many types of surgery, with different aetiologies (neuropathic vs inflammatory/nociceptive pain), often at small sizes and with very different duration and dosing of the gabapentinoids. The largest (n = 240) and most well-designed study was done in knee arthroplasty [1], in which neuropathic pain is not a highly significant clinical problem compared to other well-described operations with higher risk of nerve damage, such as thoracotomy, amputation, mastectomy with axillary dissection, and groin hernia repair. However, the knee study [1] otherwise had an optimal design with 2 weeks of postoperative treatment with pregabalin, and neuropathic pain was reduced from 8.7% to 0%, but was assessed only by the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score and based on a telephone interview. There was no exact assessment of pain scores during well-defined movements at 3- and 6-month follow-up, thereby hindering final conclusions about the actual value of gabapentinoids in this particular operation. In conclusion, the clinical studies lack an optimal design, and do not include assessment of all perioperative risk factors for persistent postsurgical pain [7]. Taken together with the additional and mostly negative experimental data, strategies other than gabapentinoids probably should be followed up to reduce persistent postsurgical neuropathic pain (nerve-sparing techniques, targeting other mechanisms, reducing neuroinflammatory response, etc.) [6]. References [1] Buvanendran A, Kroin JS, la Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010;110:199–207. [2] Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013;7:CD008307. [3] Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012;115:428–42. [4] De Felice M, Sanoja R, Wang R, Vera-Portocarrero L, Oyarzo J, King T, Ossipov MH, Vanderah TW, Lai J, Dussor GO, Fields HL, Price TJ, Porreca F. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. PAINÒ 2011;152:2701–9.
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.11.016
Ò
Bridging the gaps: Special commentary / PAIN 155 (2014) 208–209 [5] Donovan-Rodriguez T, Dickenson AH, Urch CE. Gabapentin normalizes spinal neuronal responses that correlate with behavior in a rat model of cancerinduced bone pain. Anesthesiology 2005;102:132–40. [6] Gilron I, Kehlet H. Prevention of chronic pain after surgery: new insights for future research and patient care. Can J Anaesth 2013. http://dx.doi.org/10.1007/ 107s12630-013-0067-8. [7] Kehlet H, Rathmell JP. Persistent postsurgical pain: the path forward through better design of clinical studies. Anesthesiology 2010;112:514–5. [8] Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology 2013;119:1215–21. [9] Yang F, Whang J, Derry WT, Vardeh D, Scholz J. Analgesic treatment with pregabalin does not prevent persistent pain after peripheral nerve injury in the rat. PAINÒ 2014;155:356–66.
209
⇑
Anthony H. Dickenson Neuroscience, Physiology and Pharmacology, University College London, Gower St., London, UK ⇑ Corresponding author. Tel.: +44 207 679 3742. E-mail address: [email protected] Henrik Kehlet Section for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, Denmark
PAIN 155 (2014) 208–209
www.elsevier.com/locate/pain
Bridging the gaps: Special commentary
Can we stop pain before it starts? The prevention of chronic pain has been a goal for decades, and the present study uses pregabalin to gauge its ability to prevent persistent pain after nerve injury [9]. This is a nice article that uses behaviour and immunohistochemistry to probe the effects of the drug. It failed—so should we just give up, or are there issues with this study that need to be addressed in future investigations? The authors did observe that an early treatment worked better than a delayed one, supporting the idea that treating as soon as possible has some benefits. The drug was able to suppress cold and mechanical hypersensitivity during administration, but the abnormal responsivity produced by the nerve injury rapidly returned once the drug was turned off. Few experimental studies have attempted to try to prevent persistent pain with gabapentinoids, so the present study has great value. One facet is that the pregabalin was given spinally, and although this is a major site of action of the drug, the authors failed to see a change in the target protein, the alpha-2 delta subunit. Thus it may be that systemic routes, apart from mimicking the human use of the drug, could better target the dorsal root ganglion (DRG), allowing effects on translocation to occur. This is almost what one might expect because the consequences of the peripheral origins and the subsequent central changes leading to hypersensitivity caused by the neuropathy will re-emerge as the drug wears off. Thus, there is no disease modification, only control of the symptoms. There is a fascinating finding in the present study because the animals could be rendered analgesic during exposure to pregabalin without any change in certain markers of microglial activation. This suggests some caution in attribution of pain to nonneuronal systems. However, is it always the case that the pain of nerve injury cannot be prevented beyond the pharmacological actions of the drug? Last year De Felice et al. [4], in this journal, showed that rats that could produce a sustained intrinsic noradrenergic drive were protected from the behavioural consequences of nerve injury despite a persistence of certain neuropathic markers in the DRG. However, albeit given for shorter periods, gabapentin [5] and indeed morphine, although able to normalize behavioural and neuronal changes in a model of cancer-induced bone pain, lost their effects when the drug wore off, presumably reflecting a continued peripheral drive that re-establishes the pain state. Thus no prevention of the chronic pain state appears to occur unless the modulatory system is continually activated, through either drugs or endogenous signalling. In accordance with the negative findings in the detailed experimental setup [9], the corresponding clinical studies have so far also been negative regarding potential benefits of gabapentinoids to reduce persistent postsurgical pain. Although there may be
q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.10.024
general agreement that gabapentinoids may be valuable for reduction of early postoperative pain and opioid consumption [8], the optimal dose and duration of treatment in relation to different procedures and compared to side effects still require further studies. When it comes to the potential benefits of perioperative gabapentinoids on persistent postsurgical pain, 3 major reviews have been published during the last year based on 11 to 16 randomized controlled trials [2,3,8]. It becomes clear that there is a discrepancy between the positive findings of early perioperative gabapentinoids on acute postoperative pain, because the overall data do not support any positive effects on persistent postsurgical pain. However, as stated in the reviews [2,3,8], this conclusion is based on data that unfortunately come from many types of surgery, with different aetiologies (neuropathic vs inflammatory/nociceptive pain), often at small sizes and with very different duration and dosing of the gabapentinoids. The largest (n = 240) and most well-designed study was done in knee arthroplasty [1], in which neuropathic pain is not a highly significant clinical problem compared to other well-described operations with higher risk of nerve damage, such as thoracotomy, amputation, mastectomy with axillary dissection, and groin hernia repair. However, the knee study [1] otherwise had an optimal design with 2 weeks of postoperative treatment with pregabalin, and neuropathic pain was reduced from 8.7% to 0%, but was assessed only by the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score and based on a telephone interview. There was no exact assessment of pain scores during well-defined movements at 3- and 6-month follow-up, thereby hindering final conclusions about the actual value of gabapentinoids in this particular operation. In conclusion, the clinical studies lack an optimal design, and do not include assessment of all perioperative risk factors for persistent postsurgical pain [7]. Taken together with the additional and mostly negative experimental data, strategies other than gabapentinoids probably should be followed up to reduce persistent postsurgical neuropathic pain (nerve-sparing techniques, targeting other mechanisms, reducing neuroinflammatory response, etc.) [6]. References [1] Buvanendran A, Kroin JS, la Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010;110:199–207. [2] Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013;7:CD008307. [3] Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012;115:428–42. [4] De Felice M, Sanoja R, Wang R, Vera-Portocarrero L, Oyarzo J, King T, Ossipov MH, Vanderah TW, Lai J, Dussor GO, Fields HL, Price TJ, Porreca F. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. PAINÒ 2011;152:2701–9.
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.11.016
Ò
Bridging the gaps: Special commentary / PAIN 155 (2014) 208–209 [5] Donovan-Rodriguez T, Dickenson AH, Urch CE. Gabapentin normalizes spinal neuronal responses that correlate with behavior in a rat model of cancerinduced bone pain. Anesthesiology 2005;102:132–40. [6] Gilron I, Kehlet H. Prevention of chronic pain after surgery: new insights for future research and patient care. Can J Anaesth 2013. http://dx.doi.org/10.1007/ 107s12630-013-0067-8. [7] Kehlet H, Rathmell JP. Persistent postsurgical pain: the path forward through better design of clinical studies. Anesthesiology 2010;112:514–5. [8] Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology 2013;119:1215–21. [9] Yang F, Whang J, Derry WT, Vardeh D, Scholz J. Analgesic treatment with pregabalin does not prevent persistent pain after peripheral nerve injury in the rat. PAINÒ 2014;155:356–66.
209
⇑
Anthony H. Dickenson Neuroscience, Physiology and Pharmacology, University College London, Gower St., London, UK ⇑ Corresponding author. Tel.: +44 207 679 3742. E-mail address: [email protected] Henrik Kehlet Section for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, Denmark
