Suellen M. Walker

Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm

Abstract Alterations in neural activity due to pain and injury in early development may produce long‐term effects on sensory processing and future responses to pain. To investigate persistent alterations in sensory perception, we performed quantitative sensory testing (QST) in extremely preterm (EP) children (n = 43) recruited from the UK EPICure cohort (born less than 26 weeks gestation in 1995) and in age and sex matched term‐born controls (TC; n = 44). EP children had a generalized decreased sensitivity to all thermal modalities, but no difference in mechanical sensitivity at the thenar eminence. EP children who also required neonatal surgery had more marked thermal hypoalgesia, but did not differ from non‐surgical EP children in the measures of neonatal brain injury or current cognitive ability. Adjacent to neonatal thoracotomy scars there was a localized decrease in both thermal and mechanical sensitivity that differed from EP children with scars relating to less invasive procedural interventions or from those without scars. No relationship was found between sensory perception thresholds and current pain experience or pain coping styles in EP or TC children. Neonatal care and surgery in EP children are associated with persistent modality‐specific changes in sensory processing. Decreases in mechanical and thermal sensitivity adjacent to scars may be related to localized tissue injury, whereas generalized decreases in thermal sensitivity but not in mechanical sensitivity suggest centrally mediated alterations in the modulation of C‐fibre nociceptor pathways, which may impact on responses to future pain or surgery.

Infant pain management: a developmental neurobiological approach

Infant pain is a clinical reality. Effective pain management in infants requires a specialist approach—analgesic protocols that have been designed for older children cannot simply be scaled down for CNS pain pathways and analgesic targets that are in a state of developmental transition. Here, we discuss the particular challenges that are presented by an immature CNS for the detection and treatment of pain. We show how the application of neurophysiological and neuropharmacological approaches can help to overcome the problems inherent in measuring and treating pain in infants, and how research data in these areas can be used to devise age-appropriate methods of assessing pain as well as strategies for pain relief. The evidence that untreated pain in infancy results in long-term adverse consequences is presented, thereby emphasizing the need for a longer term view of infant pain management.

The Efficacy of Intrathecal Morphine and Clonidine in the Treatment of Pain After Spinal Cord Injury

We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1–2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region. Implications Neuropathic pain after spinal cord injury is very difficult to control adequately by using currently available techniques. We have performed a placebo-controlled, double-blinded study demonstrating that administration of a combination of morphine and clonidine into the spinal fluid can provide substantial pain relief in some people with this type of pain.

Combination spinal analgesic chemotherapy: a systematic review.

In the 25 years since the first application of spinal opioids for treating cancer pain, this mode of analgesia has grown to enjoy worldwide use (1,2). A natural outgrowth of local-anesthetic spinal anesthesia, “the major advantages of ‘selective’ blockade of pain by spinal opioids [lay] in the absence of sympathetic blockade and postural hypotension, potentially allowing easy ambulation of patients, and avoidance of cardiovascular collapse or convulsions—the major complications of local anesthetic blockade” (3). Perioperative epidural analgesia is increasingly recognized to influence surgical outcomes and the likelihood of developing chronic pain states, and technical refinements in delivery systems (4) allow chronic spinal drug delivery for management of previously refractory cancer pain (5–7). Such progress reflects the rapid maturation of the practice of spinal analgesia since the previous frequently cited (8) review of this topic (3). During these same two decades, advances in preclinical pain research have led to recognition of the spinal cord as a key target for inhibition of acute nociception and preemption of “pain memory” (9). It is now clear that the customary distinction between acute and chronic pain is an oversimplification because key psychological and physiological responses traditionally associated with persistent pain (gene expression and neuronal sensitization and remodeling) rapidly follow acute injury (10). Persuasive evidence has emerged that persistent pain, regardless of its cause, constitutes a pathologic state per se in which spinal neuronal reorganization (“plasticity”) exaggerates and perpetuates nociception and pain (11–13). Insight into spinal cord pathophysiology and pharmacology has spurred novel drug discovery and rekindled interest in spinal delivery of established drugs (14,15). In an effort to gain better control over pain acutely and to maintain such control over the long term (16,17), anesthesiologists and others involved in the treatment of pain have advanced from single-drug spinal drug therapy to the coadministration of two and three drugs. Unfortunately, the standards of rigorous clinical evidence have almost wholly been ignored during this progress, and uncontrolled case series or case reports form by far the largest proportion of this literature (18). Considering that the number of possible combinations of different analgesics increases as a factorial function of the number of available choices, the optimum choices and relative doses of drugs to apply to different patient populations with different origins of pain require extensive clinical study (19). At the same time, knowledge of the neurotransmitters, membrane receptors, and intracellular mediators involved in dorsal horn nociceptive processing has evolved to reveal a remarkable diversity (Fig. 1). The growing trend of using spinal drug combinations that target multiple mechanisms of analgesia mirrors multidrug therapy in many medical disciplines and has been termed combination analgesic chemotherapy (11). This review systematically examines one emerging aspect of spinal opioid and non-opioid analgesia; namely, the application of drug combinations for spinal analgesia. We omit for space considerations other topics that have recently been reviewed (e.g., outcomes of spinal regional analgesia) (20,21), are beyond the scope of this brief survey (e.g., relative merits of Supported by the Australian National Health and Medical Research Council (SMW and MJC), the Saltonstall and Armington Funds (DBC and LCG), federal Grants National Cancer Institute R01 CA65505-04 (DBC) and Department of Defense DAMD 17-96-C6043 (DBC and LCG), and Agency for Healthcare Research and Quality Contract No. 290-97-0019 (DBC and LCG). Accepted for publication May 3, 2002. Address correspondence to D. Carr, MD, Department of Anesthesiology, Box 298, New England Medical Center, 750 Washington St., Boston, MA 02111. Address e-mail to daniel.carr@tufts.edu. Reprints will not be available from the authors.

Analysis of 50 patients with atypical odontalgia: A preliminary report on pharmacological procedures for diagnosis and treatment

Atypical odontalgia is a distressing and unusual chronic orofacial pain condition. It is often difficult to diagnose because it is associated with a lack of clinical and radiographic abnormalities. The condition is poorly understood on a pathophysiological basis, and patients often undergo repetitive and unnecessary dental procedures in attempts to alleviate pain. In this study, 50 patients diagnosed with odontalgia were evaluated by pharmacological procedures, including topical anesthetic application and phentolamine infusion. Results of these pharmacological procedures suggest that atypical odontalgia is a neuropathic pain of the oral cavity that may have a component of sympathetically maintained pain. Therapeutic trials of topical capsaicin were carried out to assess its efficacy for pain reduction. Topical capsaicin was effective in most patients.

Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn

Abnormal or excessive activity related to pain and injury in early life may alter normal synaptic development and lead to changes in somatosensory processing. The aim of the current study was to define the critical factors that determine long‐term plasticity in spinal cord afferent terminals following neonatal inflammation. Hindpaw inflammation was produced in neonatal rat pups with 5 or 25 &mgr;l 2% carrageenan, and 5 or 25 &mgr;l complete Freunds adjuvant (CFA). All groups displayed a clear inflammatory response that recovered in 2 weeks in all but the 25 &mgr;l CFA group, who had persistent chronic inflammation confirmed by histological examination of the paw at 8 weeks. The 25 &mgr;l CFA group was also the only group that displayed a significant expansion of the sciatic and saphenous nerve terminal field in lamina II of the dorsal horn at 8 weeks, using wheat‐germ agglutinin–horse radish peroxidase transganglionic labelling. This effect was not accompanied by changes in dorsal root ganglion (DRG) cell number, expression of activating transcription factor 3 (ATF3), or alterations in calcitonin gene related peptide (CGRP) or isolectin B4 binding; and was not mimicked by partial nerve damage. No long‐term change in mechanical or thermal behavioural sensory thresholds was seen in any group. Lower dose CFA caused an acute, reversible expansion of terminal fields in lamina II in neonatal animals, while CFA did not produce this effect in adults. The duration and effect of neonatal inflammation is therefore dependent on the type and volume of inflammatory agent used. The expansion of afferent terminals in lamina II following neonatal CFA inflammation is maintained into adulthood if the inflammation is also maintained, as seen following 25 &mgr;l CFA. This effect is not seen in adult animals, emphasising the plasticity of the nervous system early in development.

Intrathecal clonidine and baclofen in the management of spasticity and neuropathic pain following spinal cord injury: a case study.

Spasticity and pain are common disabling sequelae following spinal cord injury (SCI) and are often difficult to manage. The two problems are also not infrequently related. A variety of pharmacological and other approaches have been described for management of these problems in SCI. This case study reports a 32-year-old woman with an established incomplete C5 tetraplegia (anterior cord syndrome) who developed severe, intractable anal spasm following a hemorrhoidectomy, which persisted despite very good healing. This prevented evacuation of her bowels and resulted in severe rectal pain and episodes of autonomic dysreflexia. Attempts to modify the rate and mode of delivery of intrathecal baclofen through an existing programmable infusion pump failed to reduce anal sphincter spasm or improve symptoms. A right-sided pudendal block with lignocaine provided some relief. Clonidine was added to baclofen in the pump reservoir and both drugs were administered intrathecally in combination. This resulted in an immediate improvement in anal sphincter spasm and pain relief, allowing rapid reestablishment of her normal bowel pattern without need for any supplemental analgesia. It appears that intrathecal clonidine may have an important role in the treatment of spasticity, either as a single or an adjuvant agent, when intrathecal baclofen alone is ineffective or there is increasing tolerance to baclofen. Intrathecal clonidine may also prove useful in the management of intractable neuropathic pain.

Pain in children: recent advances and ongoing challenges.

Significant advances in the assessment and management of acute pain in children have been made, and are supported by an increase in the availability and accessibility of evidence-based data. However, methodological and practical issues in the design and performance of clinical paediatric trials limit the quantity, and may influence the quality, of current data, which lags behind that available for adult practice. Collaborations within research networks, which incorporate both preclinical and clinical studies, may increase the feasibility and specificity of future trials. In early life, the developing nervous system responds differently to pain, analgesia, and injury, resulting in effects not seen in later life and which may have long-term consequences. Translational laboratory studies further our understanding of developmental changes in nociceptor pathway structure and function, analgesic pharmacodynamics, and the impact of different forms of injury. Chronic pain in children has a negative impact on quality of life, resulting in social and emotional consequences for both the child and the family. Despite age-related differences in many chronic pain conditions, such as neuropathic pain, management in children is often empirically based on data from studies in adults. There is a major need for further clinical research, training of health-care providers, and increased resources, to improve management and outcomes for children with chronic pain.

Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children.

Perioperative pain in children can be effectively managed with systemic opioids, but addition of paracetamol or nonsteroidal anti‐inflammatory drugs (NSAIDs) may reduce opioid requirements and potentially improve analgesia and/or reduce adverse effects.

Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: critical period and dependence on initial afferent activity.

ABSTRACT Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury‐related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. Plantar hindpaw incision produces acute mechanical hyperalgesia in neonatal and adult rats, but incision in neonatal pups has an additional effect on the response to subsequent injury. With initial incision at postnatal day (P) 3 or 6, the degree of hyperalgesia following repeat incision 2 weeks later was greater than in animals having a single incision at the same age. At older ages (initial incision at P10, P21 or P40) responses did not differ in repeat and single incision groups. To test the role of primary afferent activity, levobupivacaine sciatic block was performed prior to P6 plantar incision, and controls received saline or subcutaneous levobupivacaine. Repeat peri‐operative, but not a single pre‐operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri‐operative analgesia used for neonatal surgery.