scholarly journals PACAP-PAC1 Receptor Inhibition is Effective in Models of Opioid-Induced Medication Overuse Headache

2021 ◽  
Author(s):  
Zachariah Bertels ◽  
Elizaveta Mangutov ◽  
Kendra Siegersma ◽  
Alycia Tipton ◽  
Amynah A Pradhan
Keyword(s):  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Opioid Use ◽  
Pac1 Receptor ◽  
Pharmacological Agents ◽  
Migraine Pain ◽  
Receptor Inhibition ◽  
Opioid Administration ◽  
Pituitary Adenylate Cyclase ◽  
Opioid Induced Hyperalgesia

AbstractOpioids are regularly prescribed for migraine and can result in medication overuse headache and dependence. We recently showed that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated following opioid administration or in a model of chronic migraine. The goal of this study was to determine if PACAP was a link between opioid use and headache chronification. We tested the effect of PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated migraine pain and aura; and examined the co-expression between mu opioid receptor (MOR), PAC1, and PACAP in headache-associated brain and peripheral regions.To model opioid exacerbated migraine pain, mice were injected daily with morphine (10 mg/kg) or vehicle for 11 days. On days 3,5,7,9, and 11 they also received the known human migraine trigger nitroglycerin (0.1 mg/kg) or vehicle. To model opioid exacerbated aura, mice were treated with vehicle or morphine twice daily for 4 days (20 mg/kg on days 1-3, 40 mg/kg on day 4), a well-established paradigm for causing opioid-induced hyperalgesia. On day 5 they underwent cortical spreading depression, a physiological correlate of migraine aura. The effect of the PAC1 inhibitor, M65 (0.1 mg/kg), was tested in these models. Fluorescent in situ hybridization was used to investigate the expression of MOR, PAC1, and PACAP.Only mice treated with combined morphine and nitroglycerin developed chronic cephalic allodynia (n=18/group). M65 reversed this hypersensitivity (n=9/group). Morphine significantly increased the number of CSD events (n=8-9/group); and M65 decreased this exacerbation by morphine (n=8-12/group). PAC1 and/or PACAP were highly co-expressed with MOR, and varied by region (n=6/group). MOR and PACAP were co-expressed in the trigeminal ganglia, while MOR and PAC1 receptor showed near complete overlap in the trigeminal nucleus caudalis and periaqueductal gray. The cortex showed similar cellular co-expression between MOR-PACAP and MOR-PAC1.These results show that opioids facilitate the transition to chronic headache through induction of PACAPergic mechanisms. Antibodies or pharmacological agents targeting PACAP or PAC1 receptor may be particularly beneficial for the treatment of opioid-induced medication overuse headache.

scholarly journals Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

Cephalalgia ◽  
2012 ◽  
Vol 33 (1) ◽  
pp. 52-64 ◽  
Author(s):  
Jacinta L Johnson ◽  
Mark R Hutchinson ◽  
Desmond B Williams ◽  
Paul Rolan
Keyword(s):  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Glial Activation ◽  
Novel Approach ◽  
Opioid Administration ◽  
Opioid Induced Hyperalgesia ◽  
Inflammatory State ◽  
Acute Headache

Introduction Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis “medication-overuse headache” (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking. Discussion Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. Conclusion Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

scholarly journals Monitoring chronic headache and medication-overuse headache prevalence in Denmark

Cephalalgia ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 6-18 ◽  
Author(s):  
Maria Lurenda Westergaard ◽  
Cathrine Juel Lau ◽  
Karen Allesøe ◽  
Signe Thorup Gjendal ◽  
Rigmor Højland Jensen
Keyword(s):  
Chronic Headache ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Cross Sectional Study ◽  
Self Report ◽  
Opioid Use ◽  
Cross Sectional ◽  
Pain Medications ◽  
High Prevalence ◽  
Survey Responses

Objectives To study chronic headache and medication-overuse headache (MOH) prevalence; to identify groups with high prevalence of these conditions; and to identify the most frequently used pain medications among respondents with chronic headache. Background Chronic headache and MOH prevalence in Denmark were last estimated in 2010. Methods In this cross-sectional study, 104,950 individuals aged ≥16 years were randomly sampled for the 2017 Danish Capital Region Health Survey. Responses to questions about headache and use of acute pain medications were linked to demographic registries. MOH was defined as headache ≥15 days/month plus self-report of use of pain medications ≥10 or 15 days/month, in the last three months. Weighted prevalence proportions were calculated. Results Among 55,185 respondents, chronic headache prevalence was 3.0% (95% CI: 2.3–3.2) and MOH prevalence was 2.0% (95% CI: 1.8–2.1). Both conditions were more common among females and the middle-aged. Respondents on social welfare or receiving early retirement pensions had the highest prevalences. Among those with chronic headache, 44.7% overused over-the-counter analgesics for headache; paracetamol 41.5%; a combination of different pain relievers 25.3%; ibuprofen 21.9%; opioids 17.0%; combination preparations 14.3%; and triptans 9.1%. Conclusions The highest prevalence of chronic headache and MOH was seen among people with low socioeconomic position. Overuse of paracetamol was most common. Reported opioid use was higher than expected. Groups with high prevalence of MOH should be the focus of public health interventions on rational use of OTC and prescription pain medications.

scholarly journals Perioperative Ketamine Infusion is Effective in Reversing Opioid-Induced Hyperalgesia

2017 ◽  
pp. 51-55
Author(s):  
Kenneth Candido
Keyword(s):  
Nmda Receptors ◽  
Direct Result ◽  
Phantom Pain ◽  
Opioid Use ◽  
Ketamine Infusion ◽  
Paradoxical Response ◽  
Arm Pain ◽  
Stump Pain ◽  
Opioid Administration ◽  
Opioid Induced Hyperalgesia

Opioid-induced hyperalgesia (OIH) is a condition of nociceptive sensitization caused by exposure to opioids, which is characterized by a paradoxical response whereby patients receiving opioids for the treatment of pain actually become more sensitive to pain as a direct result of opioid therapy. There is increasing evidence showing OIH presents a clinical challenge in acute, chronic, and cancer pain settings. Both clinical and animal studies have shown that glutamate N-methyl-Daspartate (NMDA) receptors may play a key role in OIH and pre-application of ketamine, an NMDA receptor antagonist, or co-administration of ketamine and opioids, can prevent OIH. However, no reports have shown if ketamine can reverse OIH once it occurs. We present a case of a 56-year-old male with past medical history of DM-2 with severe peripheral neuropathy, recurrent osteomyelitis of the left foot, hypertension, dyslipidemia, chronic neck and right arm pain due to cervical spondylosis, status post four times of cervical discectomy and fusion surgeries for cervical radiculopathy. He was on high doses of opioids (MS Contin 60 mg po q8 hour and hydrocodone/acetaminophen 10/325 prn- up to 4 times daily) for approximately 10 years. He underwent left below knee amputation due to uncontrolled osteomyelitis. The patient had worsening stump pain with increasing dose of opioids and phantom pain on post-operative day 1, and he developed OIH, diagnosed as escalating pain reports with every opioid dose increase. A ketamine infusion (loading dose 10 mg IV bolus, then 20 mg/hour IV infusion) was used after total cessation of opioid use for postoperative analgesia for 3 consecutive days and the patient recovered from his obvious OIH, with his stump pain and phantom pain well-controlled by opioid administration on post-operative day 5. In our case, blockage of NMDA receptors by ketamine might quickly restore the balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems by deactivation of the latter, which may help the patient recover from OIH rapidly. While it is possible that ketamine may help facilitate patients’ recovery from OIH in addition to its ability to prevent OIH, this clinical observation has to be tested in future prospective studies. Key words: Ketamin, opioid-induced hyperalgesia

scholarly journals Perioperative Ketamine Infusion is Effective in Reversing Opioid-Induced Hyperalgesia

2017 ◽  
pp. 143-148
Author(s):  
Kenneth Candido
Keyword(s):  
Nmda Receptors ◽  
Direct Result ◽  
Phantom Pain ◽  
Opioid Use ◽  
Ketamine Infusion ◽  
Paradoxical Response ◽  
Arm Pain ◽  
Stump Pain ◽  
Opioid Administration ◽  
Opioid Induced Hyperalgesia

Opioid-induced hyperalgesia (OIH) is a condition of nociceptive sensitization caused by exposure to opioids, which is characterized by a paradoxical response whereby patients receiving opioids for the treatment of pain actually become more sensitive to pain as a direct result of opioid therapy. There is increasing evidence showing OIH presents a clinical challenge in acute, chronic, and cancer pain settings. Both clinical and animal studies have shown that glutamate N-methyl-D-aspartate (NMDA) receptors may play a key role in OIH, and pre-application of ketamine, an NMDA receptor antagonist, or a co-administration of ketamine and opioids, can prevent OIH. However, no reports have shown if ketamine can reverse OIH once it occurs. We present a case of a 56-year-old male with a past medical history of DM-2 with severe peripheral neuropathy, recurrent osteomyelitis of the left foot, hypertension, dyslipidemia, chronic neck and right arm pain due to cervical spondylosis, status post 4 times of cervical discectomy, and fusion surgeries for cervical radiculopathy. He was prescribed to high doses of opioids (morphine 60 mg, orally every 8 hours and hydrocodone/acetaminophen 10/325 mg, as needed up to 4 times daily) for approximately 10 years. He underwent left below-knee amputation due to uncontrolled osteomyelitis. The patient had worsening stump pain with an increasing dose of opioids and phantom pain on post-operative day one, and he developed OIH, diagnosed as escalating pain reports with every opioid dose increase. A ketamine infusion (loading dose of 10 mg IV bolus, then 20 mg/ hour IV infusion) was used after total cessation of opioid use for post-operative analgesia for 3 consecutive days and the patient recovered from his obvious OIH, with his stump pain and phantom pain well-controlled by opioid administration on post-operative day 5. In our case, the blockage of NMDA receptors by ketamine might quickly restore the balance between opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems by deactivation of the latter, which may help the patient recover from OIH rapidly. While it is possible that ketamine may help facilitate patients’ recovery from OIH in addition to its ability to prevent OIH, this clinical observation must be tested in future prospective studies. Key words: Opioids, ketamine, opioid-induced hyperalgesia, phantom pain, post-amputation, post-operative

scholarly journals Medication-overuse headache. Retrospective comparison of preventive treatments

2018 ◽  
Vol 76 (10) ◽  
pp. 668-673 ◽  
Author(s):  
Abouch V. Krymchantowski ◽  
Ana Gabriela Ferreira Krymchantowski ◽  
Carla da Cunha Jevoux
Keyword(s):  
Retrospective Analysis ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Headache Frequency ◽  
Limited Evidence ◽  
Pharmacological Agents ◽  
Pharmacological Prevention ◽  
Retrospective Comparison ◽  
The One

ABSTRACT Objectives: Medication-overuse headache is commonly seen in tertiary centers. Limited evidence is available regarding treatment. We compared the use of one or two drugs, three drugs, or four pharmacological agents for the prevention of headache. Methods: This was a retrospective analysis of 149 consecutive patients. Sudden withdrawal and pharmacological prevention with one or more drugs were carried out. Adherence and the decrease of headache frequency of more than 50% were compared after four months between the one or two, three, and four drug groups. Results: There was no difference in adherence (p > 0.6). Headache frequency reduction was shown in 23 (54.8%, one or two drugs), 33 (70%, three drugs) and 11 (55%, four drugs); p = 0.13 and p = 0.98, not significant. There was a tendency towards significance between the one or two drug takers versus the three drug and four drug takers together (p = 0.09). Conclusions: The use of more drugs was not better at improving headache. However, there is the possibility that acting simultaneously on different sites may promote broader modulation and better outcome.

scholarly journals Medication Overuse Headache in Chronic Migraine Patients Using Cannabis: A Case-Referent Study

2021 ◽  
Author(s):  
Niushen Zhang ◽  
Yohannes W Woldeamanuel
Keyword(s):  
Chronic Migraine ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Cannabis Use ◽  
Predictor Variables ◽  
Opioid Use ◽  
Migraine Frequency ◽  
Electronic Chart ◽  
Opioid Users ◽  
Frequency Current

Abstract Objective: To examine whether cannabis use predicts medication overuse headache (MOH) in chronic migraine (CM) patients. Methods: Electronic chart review was conducted by combining the terms “chronic migraine”, “medication overuse”, “cannabis”, “CBD”, “THC” for patients seen at our headache clinics from 2015 to 2019. Of 729 charts identified, 368 (150 using cannabis; 218 not using cannabis) met our inclusion criteria, i.e., adult CM patients with ≥ 1-year CM duration. The following variables were extracted from each patient’s chart: MOH diagnosis as dependent variable, and predictor variables as age, sex, migraine frequency, current CM duration, current cannabis use duration, overused acute migraine medications, current MOH duration, and types of cannabis products used. Logistic regression was employed to identify variables predicting MOH while controlling for remaining predictors. Agglomerative hierarchical clustering (AHC) was conducted to explore natural clusters using all predictor variables. Results: There were 212 CM patients with MOH ( cases ) and 156 CM patients without MOH ( referents ). Current cannabis use statistically significantly predicted cases with MOH – odds ratio 6.0 (3.45, 10.43), p < 0.0001. Current cannabis use, opioid use, and MOH were significantly associated. AHC revealed two major natural clusters. Cluster I patients were younger with less migraine frequency, higher MOH burden, more current cannabis and opioid users than cluster II. Conclusion: Cannabis use significantly contributes to the prevalence of MOH in CM. Bidirectional cannabis-opioid association was observed – use of one increased use of the other. Advising CM patients with MOH to reduce cannabis use may help treat MOH effectively.

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