Ketamine as Treatment for Cluster Headache: A Systematic Review of Literature and a Case Series.

INTRODUCTION: Cluster headache is a severe and debilitating neurological condition characterized by intense, excruciating pain with a significant impact on patients' wellbeing. Although different treatment options are available, many patients continue to experience inadequate relief. Therefore, experimental strategies are increasingly studied. One of the more promising approaches is the use of ketamine. We present the currently available evidence and our own data. METHODS: In this mixed-methods paper, we first summarize the available evidence of ketamine for treatment of cluster headache based on a systematic review of literature in MEDLINE, EMBASE and the Cochrane library of systematic reviews. As the level of evidence is quite limited, we report our own cohort study with ten patients treated with ketamine infusions for cluster headache. They were followed up to investigate the patients' experience of treatment success and quality of life. RESULTS: The search and review of literature identified four reports with a total of 68 patients. All were uncontrolled case series. The current literature suggests that ketamine might decrease cluster headache. However, as the applied regimes and reported outcomes are highly heterogeneous, further analysis was futile. Our own data show high patient satisfaction with ketamine treatment. CONCLUSION: Despite the limited evidence, ketamine might be considered a potential therapeutic approach for cluster headache. Therefore, further research including randomized controlled trials should be encouraged.

This article discusses the potential use of ketamine for the treatment of cluster headache, a severe neurological condition that can have a significant impact on patients' quality of life. The authors conducted a systematic review of the existing literature on ketamine for the treatment of cluster headache. Additionally, they also presented their own cohort study of ten patients receiving ketamine infusions. The review of the literature revealed four reports with a total of 68 patients, all of which were uncontrolled case series. While the current literature suggests that ketamine may be effective in relieving cluster headache symptoms, the heterogeneity of treatment regimens and reported outcomes makes it difficult to draw definitive conclusions. The authors' own cohort study found that patients were very satisfied with ketamine treatment, indicating a potential benefit of this approach. However, due to the limited evidence available, further research, including randomized controlled trials, is needed to better understand the efficacy of ketamine in the treatment of cluster headaches.

The Dose-Response Relationship between Opioid Agonist Therapy and Alterations in Pain Pathways in Patients with Opioid Use Disorders: A Cross-Sectional Study.

INTRODUCTION: The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances. OBJECTIVE: The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship. METHODS: This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed. RESULTS: A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization. CONCLUSION: The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.

Calcitonin in the Treatment of Phantom Limb Pain: A Systematic Review.

INTRODUCTION: Phantom limb pain (PLP) refers to pain perceived in a part of the body removed by amputation or trauma. Despite the high prevalence of PLP following amputation and the significant morbidity associated with it, robust therapeutic approaches are currently lacking. Calcitonin, a polypeptide hormone, has recently emerged as a novel analgesic with documented benefits in the treatment of several pain-related conditions. METHODS: We present a systematic review that comprehensively evaluates the analgesic effects of calcitonin for patients with PLP. We searched MEDLINE, OLDMEDLINE, and PubMed Central databases with the key words "calcitonin" "phantom limb pain" and "phantom pain" to identify clinical studies evaluating the efficacy or effectiveness of calcitonin administration, in any form and dose, for the treatment of PLP. Additionally, Google Scholar was searched manually with the search term "calcitonin phantom limb pain". All four databases were searched from inception until 1 December 2022. The methodological quality of each included study was assessed using the Downs and Black checklist and the GRADE criteria were used to assess effect certainty and risk of bias. RESULTS: Our search identified 4108 citations, of which six ultimately met the criteria for inclusion in the synthesis. The included articles described a mix of open-label (n = 2), prospective observational cohort (n = 1), and randomized clinical trials (n = 3). The most common treatment regimen in the current literature is a single intravenous infusion of 200 IU salmon-derived calcitonin. CONCLUSION: The available evidence supported the use of calcitonin as either monotherapy or adjuvant therapy in the treatment of PLP during the acute phase, while the evidence surrounding calcitonin treatment in chronic PLP is heterogeneous. Given the limited treatment options for the management of PLP and calcitonin's relatively wide therapeutic index, further research is warranted to determine the role that calcitonin may play in the treatment of PLP and other pain disorders.

Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials.

Chronic pain is a major source of morbidity for which there are limited effective treatments. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial. We undertook a systematic review and meta-analysis to examine the efficacy of PEA as an analgesic agent for chronic pain. A systematic literature search was performed, using the databases MEDLINE and Web of Science, to identify double-blind randomized controlled trials comparing PEA to placebo or active comparators in the treatment of chronic pain. All articles were independently screened by two reviewers. The primary outcome was pain intensity scores, for which a meta-analysis was undertaken using a random effects statistical model. Secondary outcomes including quality of life, functional status, and side effects are represented in a narrative synthesis. Our literature search identified 253 unique articles, of which 11 were ultimately included in the narrative synthesis and meta-analysis. Collectively, these articles described a combined sample size of 774 patients. PEA was found to reduce pain scores relative to comparators in a pooled estimate, with a standard mean difference of 1.68 (95% CI 1.05 to 2.31, p = 0.00001). Several studies reported additional benefits of PEA for quality of life and functional status, and no major side effects were attributed to PEA in any study. The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain.

The Effect of Smoking Cessation on Acute Pain: A Systematic Review.

Smoking is a known risk factor for developing various pain-related disorders. However, acute pain often triggers the craving for cigarette consumption, resulting in a positive feedback mechanism. In addition, there is evidence of decreased pain tolerance during the early stages of abstinence. Therefore, in this study, we aimed to investigate whether a period of decreased pain tolerance and increased pain intensity occurs during smoking cessation. A systematic literature search was conducted through PubMed and Web of Science databases for controlled studies investigating the influence of smoking cessation on acute (defined as pain presentation of < 3 months) and postoperative pain. The outcomes of interest included pain perception threshold, pain tolerance, pain intensity, and postoperative opioid requirements. The search strategy yielded 1478 studies, of which 13 clinical studies met our inclusion criteria. The included studies collectively represented data from 1721 participants from four countries. Of these, 43.3% of the included individuals were females. The mean age of the included subjects was 44.2 ± 8.2 years. The duration of smoking cessation varied considerably. The shortest duration was 2 h; others investigated the effect after more than 1 month of smoking cessation. Smokers had a history of 14.6 ± 9.9 years of nicotine abuse. The mean number of daily smoked cigarettes was 17.5 ± 10.3. Most studies examined in this systematic review show a negative influence of smoking cessation on acute pain. However, the affected pain modalities, the duration of the altered pain perception, and whether male and female smokers are equally affected could not be ascertained due to high heterogeneity and few available studies.

The Effect of Palmitoylethanolamide on Pain Intensity, Central and Peripheral Sensitization, and Pain Modulation in Healthy Volunteers-A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial.

Palmitoylethanolamide (PEA) is marketed as a "dietary food for special medical purposes". Its broad-spectrum analgesic, anti-inflammatory, and neuroprotective effects make PEA an interesting substance in pain management. However, the underlying analgetic mechanisms have not yet been investigated in humans. The aim of our study is to provide a deeper understanding of the involved mechanisms, which is essential for differentiating therapeutic approaches and the establishment of mechanism-based therapeutic approaches. In this randomized, placebo-controlled, double-blinded crossover trial, 14 healthy volunteers were included. PEA (3 × 400 mg per day) or placebo were taken for 4 weeks. Our study investigated the mode of action of PEA using an established pain model, "Repetitive phasic heat application", which is well-suited to investigate analgesic and anti-hyperalgesic effects in healthy volunteers. Parameters for peripheral and central sensitization as well as for pain modulation were assessed. Repetitive heat pain was significantly decreased, and the cold pain tolerance was significantly prolonged after the PEA treatment. The pressure pain tolerance and the conditioned pain modulation were increased after the PEA treatment. The wind-up ratio and the average distance of allodynia were significantly decreased after the PEA treatment. The heat pain tolerance was significantly higher after the PEA treatment. The present study has demonstrated that PEA has clinically relevant analgesic properties, acting on both peripheral and central mechanisms as well as in pain modulation.

Google Trends for Pain Search Terms in the World's Most Populated Regions Before and After the First Recorded COVID-19 Case: Infodemiological Study.

BACKGROUND: Web-based analysis of search queries has become a very useful method in various academic fields for understanding timely and regional differences in the public interest in certain terms and concepts. Particularly in health and medical research, Google Trends has been increasingly used over the last decade. OBJECTIVE: This study aimed to assess the search activity of pain-related parameters on Google Trends from among the most populated regions worldwide over a 3-year period from before the report of the first confirmed COVID-19 cases in these regions (January 2018) until December 2020. METHODS: Search terms from the following regions were used for the analysis: India, China, Europe, the United States, Brazil, Pakistan, and Indonesia. In total, 24 expressions of pain location were assessed. Search terms were extracted using the local language of the respective country. Python scripts were used for data mining. All statistical calculations were performed through exploratory data analysis and nonparametric Mann-Whitney U tests. RESULTS: Although the overall search activity for pain-related terms increased, apart from pain entities such as headache, chest pain, and sore throat, we observed discordant search activity. Among the most populous regions, pain-related search parameters for shoulder, abdominal, and chest pain, headache, and toothache differed significantly before and after the first officially confirmed COVID-19 cases (for all, P<.001). In addition, we observed a heterogenous, marked increase or reduction in pain-related search parameters among the most populated regions. CONCLUSIONS: As internet searches are a surrogate for public interest, we assume that our data are indicative of an increased incidence of pain after the onset of the COVID-19 pandemic. However, as these increased incidences vary across geographical and anatomical locations, our findings could potentially facilitate the development of specific strategies to support the most affected groups.

Perioperative use of physostigmine to reduce opioid consumption and peri-incisional hyperalgesia: a randomised controlled trial.

BACKGROUND: Several studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing postoperative opioid consumption. In addition, the anti-cholinesterase drug physostigmine that increases synaptic acetylcholine concentrations has anti-inflammatory effects. METHODS: In this randomised placebo-controlled trial including 110 patients undergoing nephrectomy, we evaluated the effects of intraoperative physostigmine 0.5 mg h-1 i.v. for 24 h on opioid consumption, hyperalgesia, pain scores, and satisfaction with pain control. RESULTS: Physostigmine infusion did not affect opioid consumption compared with placebo. However, the mechanical pain threshold was significantly higher (2.3 [sd 0.3]) vs 2.2 [0.4]; P=0.0491), and the distance from the suture line of hyperalgesia (5.9 [3.3] vs 8.5 [4.6]; P=0.006), wind-up ratios (2.2 [1.5] vs 3.1 [1.5]; P=0.0389), and minimum and maximum postoperative pain scores at 24 h (minimum 1.8 [1.0] vs 2.4 [1.2]; P=0.0451; and maximum 3.2 [1.4] vs 4.2 [1.4]; P=0.0081) and 48 h (minimum 0.9 [1.0] vs 1.6 [1.1]; P=0.0101; and maximum 2.0 [1.5] vs 3.2 [1.6]; P=0.0029) were lower in the study group. Pain Disability Index was lower and satisfaction with pain control was higher after 3 months in the physostigmine group. CONCLUSIONS: In contrast to previous trials, physostigmine did not reduce opioid consumption. As pain thresholds were higher and hyperalgesia and wind-up lower in the physostigmine group, we conclude that physostigmine has anti-hyperalgesic effects and attenuates sensitisation processes. Intraoperative physostigmine may be a useful and safe addition to conventional postoperative pain control. CLINICAL TRIAL REGISTRATION: EudraCT number 2012-000130-19.

The Effect of Low-Level Light Therapy on Capsaicin-Induced Peripheral and Central Sensitization in Healthy Volunteers: A Double-Blinded, Randomized, Sham-Controlled Trial.

INTRODUCTION: Several clinical trials have demonstrated that low-level light therapy (LLLT), a method of photobiomodulation, is an effective analgetic treatment. However, the mechanism of action has not yet been finally clarified. In particular, unanswered questions include whether it only affects peripheral or whether it also affects the spinal or supraspinal level. This study aimed to evaluate the effect of low-level light therapy on primary and secondary hyperalgesia in a human pain model. METHODS: This study was planned as a randomized, sham-controlled, and double-blinded trial with repeated measures within subject design. Capsaicin was applied on both forearms of ten healthy volunteers to induce peripheral and central sensitization. One forearm was treated with low-level light therapy; the other served as sham control. RESULTS: Low-level light therapy significantly increased the mechanical pain threshold, heat pain threshold, and decreased pain intensity. CONCLUSIONS: Our data indicate that low-level light therapy is effective at reducing the heat and mechanical pain threshold in a human pain model, pointing to a significant modulating effect on peripheral and central sensitization. These effects-especially in the absence of reported side effects-make low-level light therapy a promising tool in pain management. The application of low-level light therapy to treat chronic pain should be considered for further clinical trials.

Opioid-induced constipation: a narrative review of therapeutic options in clinical management.

Pain therapy often entails gastrointestinal adverse events. While opioids are effective drugs for pain relief, the incidence of opioid-induced constipation (OIC) varies greatly from 15% to as high as 81%. This can lead to a significant impairment in quality of life, often resulting in discontinuation of opioid therapy. In this regard, a good doctor-patient relationship is especially pivotal when initiating opioid therapy. In addition to a detailed history of bowel habits, patient education regarding the possible gastrointestinal side effects of the drugs is crucial. In addition, the bowel function must be regularly evaluated for the entire duration of treatment with opioids. Furthermore, if the patient has preexisting constipation that is well under control, continuation of that treatment is important. In the absence of such history, general recommendations should include sufficient fluid intake, physical activity, and regular intake of dietary fiber. In patients of OIC with ongoing opioid therapy, the necessity of opioid use should be critically reevaluated in terms of an with acceptable quality of life, particularly in cases of non-cancer pain. If opioids must be continued, lowering the dose may help, as well as changing the type of opioid. If these measures do not suffice, the next step for persistent OIC is the administration of laxatives. If these are ineffective as well, treatment with peripherally active µ-opioid receptor antagonists should be considered. Enemas and irrigation are emergency measures, often used as a last resort.