Lucy Chen

Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression

Pain and depression are frequently comorbid disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in this comorbidity. We found that chronic pain in rats induced depressive behavior and IDO1 upregulation in the bilateral hippocampus. Upregulation of IDO1 resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. We observed elevated plasma IDO activity in patients with both pain and depression, as well as in rats with anhedonia induced by chronic social stress. Intra-hippocampal administration of IL-6 in rats, in addition to in vitro experiments, demonstrated that IL-6 induces IDO1 expression through the JAK/STAT pathway. Further, either Ido1 gene knockout or pharmacological inhibition of hippocampal IDO1 activity attenuated both nociceptive and depressive behavior. These results reveal an IDO1-mediated regulatory mechanism underlying the comorbidity of pain and depression and suggest a new strategy for the concurrent treatment of both conditions via modulation of brain IDO1 activity.

Altered quantitative sensory testing outcome in subjects with opioid therapy

ABSTRACT Preclinical studies have suggested that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred as opioid‐induced hyperalgesia (OIH). While OIH may have implications in acute and chronic pain management, its clinical features remain unclear. Using an office‐based quantitative sensory testing (QST) method, we compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects: those with neither pain nor opioid therapy (group 1), with chronic pain but without opioid therapy (group 2), and with both chronic pain and opioid therapy (group 3). We also examined the possible correlation between QST responses to thermal stimulation and opioid dose, opioid treatment duration, opioid analgesic type, pain duration, or gender in group 3 subjects. As compared with both group 1 (n = 41) and group 2 (n = 41) subjects, group 3 subjects (n = 58) displayed a decreased heat pain threshold and exacerbated temporal summation of the second pain to thermal stimulation. In contrast, there were no differences in cold or warm sensation among three groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of the second pain in group 3 subjects. These results indicate that decreased heat pain threshold and exacerbated temporal summation of the second pain may be characteristic QST changes in subjects with opioid therapy. The data suggest that QST may be a useful tool in the clinical assessment of OIH.

Combination therapy for neuropathic pain: a review of current evidence.

Neuropathic pain is a debilitating chronic condition that remains very difficult to treat. Recently, a number of clinical studies have compared the effectiveness of combination drug therapy with monotherapy for neuropathic pain treatment. In this article, we summarize up-to-date clinical studies of combination therapy for the treatment of both cancer- and non-cancer-related neuropathic pain. Despite a relatively small number of clinical studies on this topic, several positive indications have emerged. First, clinical studies using gabapentin (five positive trials) and pregabalin (five positive trials and one negative trial) in combination with an opioid, cyclo-oxygenase-2 inhibitor or antidepressant have shown positive responses greater than the respective monotherapies for pain related to diabetic neuropathy and post-herpetic neuropathy. Second, high-concentration (8%) topical capsaicin and a 5% lidocaine patch seem to be effective add-on therapies (a modality of combination therapy) for various neuropathic pain conditions. Third, combination therapy for cancer-related neuropathic pain has yielded only limited success based on a number of small-scale clinical studies.While there are benefits of using combination therapy for neuropathic pain treatment, including better pain relief and reduced adverse effects, more clinical studies are required in order to (i) make head-to-head comparisons between combination and single-drug therapies, (ii) identify symptom-specific combination therapies for distinctive clinical neuropathic pain conditions, (iii) explore combination therapies that include non-drug modalities such as physical therapy, psychological coping and biofeedback to facilitate functional restoration and (iv) develop new and objective evaluation tools for clinical outcome assessment.

The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus.

Background and Objectives: The concept of opioid‐induced hyperalgesia has recently gained prominence as a contributing factor for opioid tolerance and long‐term treatment failure. But whereas the preclinical data for this phenomenon are strong, the mixed clinical data derive primarily from experimental pain models conducted in volunteers and heroin addicts, and nonstandardized clinical stimuli, e.g., surgery. The primary objective of this study is to delineate the effect of opioid dose and treatment duration on pain intensity and unpleasantness ratings following a standardized clinical pain stimulus. Methods: Three hundred and fifty‐five patients, on a steady regimen of analgesic medications and scheduled for an interventional procedure, received a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic. Before and immediately following the injection, subjects were asked to rate pain and unpleasantness intensity on a 0 to 10 numerical rating scale. Subjects were stratified into 6 groups based on opioid dosage. A control group of 27 volunteers who had no pain and were taking no analgesics were also injected. Results: Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity was also positively associated with both outcome variables. Gender was found to be associated with pain intensity and unpleasantness, with females scoring higher in both categories than males. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. Conclusions: The results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy. This simple clinical model may provide a useful tool in examining opioid‐induced hyperalgesia.

Improved Opioid Analgesic Effect Following Opioid Dose Reduction

INTRODUCTION Traditionally, opioids have been the cornerstone of therapy for patients suffering from cancer pain, regardless of the potential to develop opioid tolerance. In chronic pain patients who experience worsening pain despite increasing doses of opioids, the clinical role of opioid-induced hyperalgesia is gaining more recognition. CASE Presented here is the case of a 56-year-old man with recurrent squamous cell lung carcinoma and spinal metastases, suffering with intractable 8/10 pain on the visual analog scale in his chest, lower thoracic spine, and upper lumbar spine. He was admitted five times for pain control. In spite of escalating doses of oxycodone, morphine, and hydromorphone, the patient continued to experience severe pain. Also, he endured undesirable sedation, fatigue, and generalized weakness. The clinical picture suggested the possibility of opioid-induced hyperalgesia. We decreased the hydromorphone dose by 40-50% and started methadone. The patients pain level dropped to a more acceptable 3/10. He was more alert, and his pain was tolerable until his death. DISCUSSION Opioid-induced hyperalgesia might be considered in a patient who has no evidence of disease progression, who is on clinically reasonable doses of opioids, and whose pain escalates as opioid doses are increased. A reduction of opioids and the addition of a low-dose N-methyl-D-aspartate receptor antagonist may provide a favorable clinical outcome in those patients who have failed to benefit from opioid rotation and other adjunctive pain treatments.

Buprenorphine-naloxone therapy in pain management.

Buprenorphine–naloxone (bup/nal in 4:1 ratio; Suboxone®; Reckitt Benckiser Pharmaceuticals Incorporation, Richmond, VA) is approved by the Food and Drug Administration for outpatient office-based addiction treatment. In the past few years, bup/nal has been increasingly prescribed off-label for chronic pain management. The current data suggest that bup/nal may provide pain relief in patients with chronic pain with opioid dependence or addiction. However, the unique pharmacological profile of bup/nal confers it to be a weak analgesic that is unlikely to provide adequate pain relief for patients without opioid dependence or addiction. Possible mechanisms of pain relief by bup/nal therapy in opioid-dependent patients with chronic pain may include reversal of opioid-induced hyperalgesia and improvement in opioid tolerance and addiction. Additional studies are needed to assess the implication of bup/nal therapy in clinical anesthesia and perioperative pain management.

Exacerbated mechanical hyperalgesia in rats with genetically predisposed depressive behavior: role of melatonin and NMDA receptors.

Summary The melatonin system dysfunction and the upregulated NMDA receptors in trigeminal nuclei might be involved in trigeminal pain and depression comorbidity. ABSTRACT A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. This study showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar‐Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior in the same WKY rats. As compared with Wistar rats, WKY rats showed a lower plasma melatonin level, downregulation of the melatonin MT1 receptor, but upregulation of the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal subnucleus caudalis (Sp5C). Intracisternal administration of 6‐chloromelatonin (250 μg, twice daily for 7 days) concurrently attenuated mechanical hyperalgesia and depressive behavior in WKY rats as well as downregulated the NR1 expression in the ipsilateral Sp5C. In patch‐clamp recordings, melatonin dose‐dependently decreased NMDA‐induced currents in spinal cord dorsal horn substantia gelatinosa neurons. These results demonstrate a reciprocal relationship between TMJ inflammation‐induced mechanical hyperalgesia and depressive behavior and suggest that the central melatoninergic system, through modulation of the NMDA receptor expression and activity, may play a role in the mechanisms of the comorbidity between pain and depression.

Persistent nociception induces anxiety-like behavior in rodents: Role of endogenous neuropeptide S

Summary Persistent nociception following nerve injury induces anxiety‐like behavior possibly mediated by the alteration of endogenous neuropeptide S. ABSTRACT Anxiety disorder is a comorbid condition of chronic pain. Analgesics and anxiolytics, subject to addiction and abuse, are currently used to manage pain and anxiety symptoms. However, the cellular mechanism underlying chronic pain and anxiety interaction remains to be elucidated. We report that persistent nociception following peripheral nerve injury induced anxiety‐like behavior in rodents. Brain expression and release of neuropeptide S (NPS), a proposed endogenous anxiolytic peptide, was diminished in rodents with coexisting nociceptive and anxiety‐like behaviors. Intracerebroventricular administration of exogenous NPS concurrently improved both nociceptive and anxiety‐like behaviors. At the cellular level, NPS enhanced intra‐amygdaloidal inhibitory transmission by increasing presynaptic gamma‐aminobutyric acid (GABA) release from interneurons. These findings indicate that the interaction between nociceptive and anxiety‐like behaviors in rodents may be regulated by the altered NPS‐mediated intra‐amygdaloidal GABAergic inhibition. The data suggest that enhancing the brain NPS function may be a new strategy to manage comorbid pain and anxiety.

Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization.

Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

Increased Pain Sensitivity in Chronic Pain Subjects on Opioid Therapy: A Cross-Sectional Study Using Quantitative Sensory Testing

OBJECTIVE The aim of this study was to compare the sensitivity to experimental pain of chronic pain patients on opioid therapy vs chronic pain patients on non-opioid therapy and healthy subjects by quantitative sensory testing (QST). SETTING There is a growing body of evidence demonstrating that chronic use of opioid drugs may alter pain sensitivity. Identifying the characteristic changes in thermal pain sensitivity in chronic opioid users will be helpful in diagnosing pain sensitivity alterations associated with chronic opioid use. METHODS Utilizing an office-based QST technique, we examined thermal pain threshold, tolerance, and temporal summation in 172 chronic pain subjects receiving opioid therapy, 121 chronic pain subjects receiving non-opioid therapy, and 129 healthy subjects. RESULTS In chronic pain subjects receiving opioid therapy, there were detectable differences in QST characteristics compared with both chronic pain subjects receiving non-opioid therapy and healthy subjects. Specifically, in chronic pain subjects receiving opioid therapy, 1) sensitivity to heat pain was increased; threshold to heat pain was significantly lower; 2) tolerance to supra-threshold heat pain was significantly decreased; and 3) temporal pain summation was exacerbated, as compared with chronic pain subjects receiving non-opioid therapy. In a subgroup of chronic pain subjects receiving opioid therapy with increased heat pain sensitivity, their average opioid medication dosage was significantly higher than those who had an above-average heat pain threshold. Moreover, a subset of chronic pain subjects on opioid therapy exhibited a significant decrease in diffuse noxious inhibitory control (DNIC) compared with chronic pain subjects on non-opioid therapy. CONCLUSION These findings suggest that a subset of QST parameters can reflect opioid-associated thermal pain sensitivity alteration, including decreased heat pain threshold, decreased cold and heat pain tolerance, diminished DNIC, and/or exacerbated temporal summation.