Neuropathic pain after thoracotomy: Tracking signs and symptoms before and at monthly intervals following surgery.

BACKGROUND: As the development of neuropathic symptoms contributes to pain severity and chronification after surgery, their early prediction is important to allow targeted treatment. OBJECTIVES: We longitudinally investigated trajectories of signs and symptoms in patients undergoing thoracotomy and assessed whether and at which time they were related to the development of neuropathic pain symptoms 6 months after surgery. METHODS: Presurgical and 6 monthly postsurgical assessments included questionnaires for mental and physical well-being (e.g., depression/anxiety, pain catastrophizing, sleep quality, neuropathic pain symptoms), and quantitative sensory testing (QST). RESULTS: QST trajectories indicated nerve impairment of the surgery site with predominant loss of function. Signs of recovery towards the end of the assessment period were observed for some tests. Unsupervised cluster analysis with NPSI scores 6 months after surgery as clustering variable identified one group with no/low levels of neuropathic symptoms and one with moderate levels. The two groups differed w.r.t. several signs and symptoms already at early time points. Notably, neuropathic pain anywhere in the body differed already preoperatively and sleep impairment differentiated the two groups at all time points. Regression analysis revealed three factors that seemed particularly suited to predicted 6 months NPSI scores, namely preoperative neuropathic pain symptoms, with contributions from sleep impairment 1 month after surgery and the presence of dynamic mechanical allodynia 3 months after surgery. CONCLUSIONS: Clinical routine should focus on the individual's physiological state, including pre-existing neuropathic pain and sleep quality to identify patients early who might be at risk to develop chronic post-surgical neuropathic pain. SIGNIFICANCE: Development of neuropathies contributes to pain severity and pain chronification after surgery. Here we demonstrate trajectories of quantitative sensory tests (assessed at monthly intervals for 6 months after surgery) that reveal accurate time courses of gain/loss of nerve function following thoracotomy. Independent of the degree of neuropathic signs after surgery, the main predictors for post-surgical neuropathic pain are self-reported neuropathic pain before surgery and sleep quality shortly after surgery.

Chronic Osteoporotic Pain in Mice: Cutaneous and Deep Musculoskeletal Pain Are Partially Independent of Bone Resorption and Differentially Sensitive to Pharmacological Interventions.

Although the pathological changes in osteoporotic bones are well established, the characterization of the osteoporotic pain and its appropriate treatment are not fully elucidated. We investigated the behavioral signs of cutaneous and deep musculoskeletal pain and physical function; time-dependent changes in bone mineral density (BMD) and the emergence of the behavioral phenotype; and the effects of pharmacological interventions having different mechanisms of action (chronic intraperitoneal administration of pamidronate [0.25 mg/kg, 5x/week for 5 weeks] versus acute treatment with intraperitoneal morphine [10 mg/kg] and pregabalin [100 mg/kg]) in a mouse model of ovariectomized or sham-operated mice 6 months following surgery. We observed reduced BMD associated with weight gain, referred cutaneous hypersensitivity, and deep musculoskeletal pain that persisted for 6 months. Chronic bisphosphonate treatment, 6 months after ovariectomy, reversed bone loss and hypersensitivity to cold, but other behavioral indices of osteoporotic pain were unchanged. While the efficacy of acute morphine on cutaneous pain was weak, pregabalin was highly effective; deep musculoskeletal pain was intractable. In conclusion, the reversal of bone loss alone is insufficient to manage pain in chronic osteoporosis. Additional treatments, both pharmacological and nonpharmacological, should be implemented to improve quality of life for osteoporosis patients.

Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical hypersensitivity and cognitive impairment in mice.

Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive impairment further impact quality of life. Chronic pain is associated with reversible changes in brain anatomy and function and with long-term changes in gene expression. Epigenetic mechanisms, including DNA methylation, contribute to wide-spread and long-lasting reprogramming of gene expression. We previously reported decreases in global DNA methylation in the mouse frontal cortex 6 months after induction of neuropathic pain using the spared nerve injury (SNI) model. Here, we examined the therapeutic effect of increasing DNA methylation using the methyl donor S-adenosylmethionine (SAM). S-adenosylmethionine is marketed as a nutritional supplement for a range of conditions including liver disease, depression, osteoarthritis, fibromyalgia, and dementia. Three months after SNI or sham surgery, animals were treated with SAM (20 mg/kg, 3×/week) or saline orally for 4 months, and the impact on sensory, motor, motivational, and cognitive indices was measured. S-adenosylmethionine attenuated SNI-induced mechanical hypersensitivity and reduced active avoidance of mechanical stimuli but had no effect on cold sensitivity or motor capacity. S-adenosylmethionine completely blocked nerve injury-induced cognitive impairment and attenuated SNI-induced decreases in global DNA methylation in the frontal cortex. In summary, chronic oral administration of the methyl donor, SAM, attenuated sensory and cognitive symptoms associated with nerve injury in mice. These effects may be mediated, in part, through modulation of DNA methylation in the central nervous system by systemic administration of the methyl donor SAM.

Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.

Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the α2A-AR. Drugs were administered intrathecally in wild type (WT) and α2A-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The α2A-AR agonist clonidine was less effective in α2A-KO mice in both assays. The absence of the α2A-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in α2A-KO mice, indicating that the α2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in α2A-KO mice, suggesting that endogenous norepinephrine acts through the α2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free α2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied α2A-ARs potentiate opioid analgesia, while non-occupied α2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management.

Nerve injury causes long-term attentional deficits in rats.

Human chronic pain sufferers frequently report problems with attention and concentration that affect daily functioning and quality of life. Chronic pain is also commonly associated with anxiety and depression. It is currently not known if the pain causes these co-morbidities, or if they are pre-disposing risk factors for the development of chronic pain. Animal studies suggest a possible causative effect of pain on cognition, but usually tests are conducted during acute ongoing pain when the pain may act as a distracter to normal cognitive and emotional processing. Here we examine long-term effects of nerve injury on cognitive functioning in a rat model, which contributes to better understanding of the relationship between cognitive impairment and chronic pain experience in human populations. This study investigated attentional capability, anxiety-like behavior and sensory functioning 6 months after spared nerve injury (SNI) surgery-a time-point well beyond the acute pain phase and akin to decades of pain experience in humans. Male Long Evans rats subjected to nerve injury remained hypersensitive to sensory stimuli from the time of injury to the 6-month post-injury assessment. At 6 months they were impaired on a visual non-selective, non-sustained attention task and displayed anxiety-like behaviors in the elevated plus maze. These findings show that cognitive disturbances observed during acute pain persist for months in a rodent chronic pain model and suggest that cognitive alterations in chronic pain patients are at least partially caused by the chronic pain state.

Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice.

Chronic low back pain (LBP) is a complex, multifactorial disorder with unclear underlying mechanisms. In humans and rodents, decreased expression of secreted protein acidic rich in cysteine (SPARC) is associated with intervertebral disc (IVD) degeneration and signs of LBP. The current study investigates the hypothesis that IVD degeneration is a risk factor for chronic LBP. SPARC-null and age-matched control mice ranging from 6 to 78 weeks of age were evaluated in this study. X-ray and histologic analysis revealed reduced IVD height, increased wedging, and signs of degeneration (bulging and herniation). Cutaneous sensitivity to cold, heat, and mechanical stimuli were used as measures of referred (low back and tail) and radiating pain (hind paw). Region specificity was assessed by measuring icilin- and capsaicin-evoked behaviour after subcutaneous injection into the hind paw or upper lip. Axial discomfort was measured by the tail suspension and grip force assays. Motor impairment was determined by the accelerating rotarod. Physical function was evaluated by voluntary activity after axial strain or during ambulation with forced lateral flexion. SPARC-null mice developed (1) region-specific, age-dependent hypersensitivity to cold, icilin, and capsaicin (hind paw only), (2) axial discomfort, (3) motor impairment, and (4) reduced physical function. Morphine (6 mg/kg, i.p.) reduced cutaneous sensitivity and alleviated axial discomfort in SPARC-null mice. Ageing SPARC-null mice mirror many aspects of the complex and challenging nature of LBP in humans and incorporate both anatomic and functional components of the disease. The current study supports the hypothesis that IVD degeneration is a risk factor for chronic LBP.

Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function.

Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans.

Experimental studies of potential analgesics for the treatment of chemotherapy-evoked painful peripheral neuropathies.

OBJECTIVE: We investigated potential analgesics for chemotherapy-evoked neuropathic pain using rats treated with paclitaxel. DESIGN: Drugs were tested in a repeated dosing paradigm (four daily injections). Topiramate was tested with a long-term treatment paradigm (12 days). A literature search was performed to summarize prior data. MEASURES: Mechanical stimulation of the hind paw was used to assay antiallodynic and antihyperalgesic effects acutely and 24 hours after injection. RESULTS: Amitriptyline produced significant analgesia, but this was not apparent until after the second injection. Baclofen produced significant effects, but the response varied erratically. Mexiletine and NMED-126 (a mixed N- and T-type calcium channel blocker) produced consistent, significant analgesia when tested acutely, but the pain relief did not persist at 24 hours postinjection. Oxcarbazepine had no effect at any time. Tramadol produced consistent, near-complete analgesia when tested acutely, but the analgesia did not persist to 24 hours postinjection. Topiramate produced significant effects that were first evident after 6-8 days of dosing. CONCLUSIONS: The present data and data from the literature review suggest that there are several potential treatments for chemotherapy-evoked neuropathic pain. Nonsteroidal anti-inflammatory drugs have little or no efficacy. Opioids have an effect, but probably only with high doses. At least some antidepressants are analgesic in these conditions. Some, but clearly not all, anticonvulsants and sodium channel blockers have efficacy. Tramadol is a particularly promising candidate. Topiramate, acetyl-L-carnitine, carbamazepine, and venlafaxine may have protective or restorative effects. Clinical trials of these candidates are needed to advance the treatment of chemotherapy-evoked pain.