Human Studies

Enhanced recovery after surgery (ERAS) program improves immediate recovery. Beyond immediate benefits, long-term impact of ERAS implementation is not yet evident. This retrospective single-center cohort study investigates prevalence and characteristics of chronic post-surgical pain (CPSP) in patients who underwent colon surgery.

Residual lower-limb pain after low back surgery (postsurgical sciatica) and complex regional pain syndrome (CRPS) involving a lower limb are separate conditions but may share some mechanisms (eg, tissue inflammation, neuroimmune disturbances, and central neuroplasticity). As adrenergically evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to postsurgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with postsurgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all 4 limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in postsurgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick, and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuroplastic changes are involved not only in the pathophysiology of CRPS but also in postsurgical sciatica. This may have treatment implications for patients with postsurgical sciatica.

The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.

Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Since the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in neural representation of MR occur between CRPS patients and healthy controls. Therefore we included 15 chronic CRPS patients and 15 age-/gender matched healthy controls. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (DASH) and MRI (T1, fMRI during MR) data. Reaction times in the patient group were delayed compared to healthy controls without a lateralization effect for affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. CRPS patients showed a reduction of fMRI activation in areas including subthalamic nucleus, nucleus accumbens and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and n. accumbens activation for MR performance. This study highlights the reduced access of CRPS patients for mental resources modulating arousal, emotional response and subcortical sensorimotor integration. PERSPECTIVE: This study localized the underlying neural responses for impaired mental rotation (MR) in patients with complex regional pain syndrome (CRPS) as a decrease in basal ganglia (putamen) and nucleus accumbens activation.

To evaluate the benefit of adding occupational therapy or physiotherapy interventions to a standard rehabilitation programme targeted for chronic widespread pain.