CORRESPONDENCE Sickle cell pain management: are we missing the role of pronociception and neuropathic pain? SIR—We read with interest the review article by Neri et al. (1) on the role of low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. This is a very important clinical problem as pain represents the cardinal complaint of patients with sickle cell disease (SCD) and is also the principle cause of hospital admission throughout their lives (2). While we agree with the authors that treatment of sickle cell pain might represent a challenge to many physicians, their assertion that there is no drug available to completely alleviate sickle cell crisis pain may not be entirely accurate. In the background of SCD pain, similar to cancer pain, these presentations are often multifactorial and vary with psychological, social, and cultural factors as well (1,2). In general, the pain level of acute sickle cell crises is high; hence, it is reasonable that opioid analge- sics are placed as first-line treatment in these situations by the published guidelines. However, some of these patients do not respond to high doses of opioids. Esca- lating the opioid doses rapidly in these patients may induce acute tolerance and opioid-induced hyperalgesia (1). The authors suggested that ketamine can oppose this effect of opioids and refer to a case series where add- ing low dose of ketamine was effective in the manage- ment of sickle cell painful crisis (1). What we like to highlight in this response is that there is an important component in the pathophysiol- ogy of pain in these patients with SCD: the neuropathic element of pain. Patients with sickle cell disease usually display nociceptive, as well as central and peripheral neuropathic types of pain. In fact, around 90% of patients described some elements of neuropathic pain including hyperalgesia and/or allodynia (3). There is emerging evidence from studies about the neurobiologi- cal mechanisms of pain in SCD suggesting a neuro- pathic component of pain in these patients (3,4). This type of pain can itself be due to occlusion of vasa vaso- rum of a peripheral nerve or spinal cord infarction. Glia activation might also participate in the predisposi- tion to neuropathic pain in these patients. This state of hyperexcitability or ‘pronociception’ may be manifested as hyperalgesia and allodynia (2,3). Laboratory evi- dence from experiments on transgenic sickle cell mice supports the neuropathic role in sickle cell patients in addition to the existing vaso-occlusive events and subsequent tissue ischemia (4). These findings of neuropathic pain in patients with SCD might have a great impact on our treatment of SCD pain as they cor- rect the common understanding that this pain is purely nociceptive. The presence of neuropathic pain in some of these patients may explain both observations made by Neri et al.—opioids alone are often ineffective, and ketamine may be useful for managing the pain of these patients. In our experience, the presence of pronociception requires addition of medications from one or more of these five groups of medications—NMDA antagonists (ketamine or memantine), anticonvulsants (pregabalin), antidepressants(nortryptiline), centrally acting alpha agonists (clonidine and dexmedetomidine), and systemic lidocaine (5,6). We believe that the under usage of these antinociceptive modalities may be the cause behind the incomplete relief of pain observed in many patients with SCD-related painful crises. In addition, these medica- tions have been shown to be effective in other models of ischemic pain and may additionally prevent the progres- sion from acute to chronic pain (5,7). Epidural analgesia was shown to be helpful in treating pain, improving oxygen saturation, and resolving pria- pism during acute crisis in pediatric patient with SCD (8,9). The vasodilator effect of epidural analgesia proba- bly helps in improving tissue and nerve ischemia in addition to its direct analgesic effect. Finally, it might be helpful to implement antipronoci- ceptive medications in combination with opioids to improve SCD patients’ pain management. Further stud- ies are required to convert accumulating experience into clinical evidence and confirm the role of neuropathic medications in SCD pain management. Acknowledgments No funding was received for this letter. Conflict of interest No conflicts of interest declared. Qutaiba A. Tawfic, Ali S.Faris & Naveen Eipe Department of Anesthesiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada Email: drqutaibaamir@yahoo.com doi:10.1111/pan.12269 © 2013 John Wiley & Sons Ltd Pediatric Anesthesia 23 (2013) 1104–1107 1104