Relationship Between Nociplastic Pain Involvement and Medication Use, Symptom Relief, and Adverse Effects Among People Using Medical Cannabis for Chronic Pain.

OBJECTIVES: Cannabis is increasingly being used for chronic pain management, but cannabis' effects remain poorly characterized in chronic nociplastic pain (NPP), which is posited to be caused by disturbances in nervous system pain processing. In this cross-sectional study (n=1213), we used the 2011 Fibromyalgia (FM) Survey Criteria as a surrogate measure for degree of NPP among individuals using medical cannabis for chronic pain. METHODS: Using a quartile-split, we investigated associations between the degree of NPP and medication use, cannabis use characteristics, and symptom relief. Continuous variables were assessed using one-way analysis of variance and categorical variables with Pearson χ 2 test and binomial logistic regression for calculation of odds ratios. RESULTS: Participants were predominately female (59%), with a mean ± SD age of 49.4±13.6 years. Higher FM scores were associated with less self-reported improvement in pain and health since initiating medical cannabis use, as well as more cannabis-related side effects. Paradoxically, higher FM scores were also associated with higher usage of concomitant medication use (including opioids and benzodiazepines) but also with substituting cannabis for significantly more medication classes, including opioids and benzodiazepines. DISCUSSION: This article presents evidence that individuals in higher NPP quartiles have higher analgesic intake, higher odds of substituting cannabis for medications, higher side effect burden, and lower therapeutic effect from cannabis. These seemingly contradictory findings may reflect higher symptom burden, polypharmacy at baseline, or that NPP may be challenging to treat with cannabis. Further research is necessary to further explain cannabinoid effects in NPP.

A mixed methods analysis of cannabis use routines for chronic pain management.

BACKGROUND: The wide heterogeneity of available cannabis products makes it difficult for physicians to appropriately guide patients. In the current study, our objective was to characterize naturalistic cannabis use routines and explore associations between routines and reported benefits from consuming cannabis. METHODS: We performed a mixed methods analysis of n=1087 cross-sectional survey responses from adults with self-reported chronic pain using cannabis for symptom management in the USA and Canada. First, we qualitatively analyzed responses to an open-ended question that assessed typical cannabis use routines, including administration routes, cannabinoid content, and timing. We then sub-grouped responses into categories based on inhalation (smoking, vaporizing) vs. non-inhalation (e.g., edibles). Finally, we investigated subgroups perceptions of how cannabis affected pain, overall health, and use of medications (e.g., substituting for opioids, benzodiazepines). Substitutions were treated as a count of medication classes, while responses for both pain and health were analyzed continuously, with - 2 indicating health declining a lot or pain increasing a lot and 2 indicating that health improved a lot or pain decreased a lot. RESULTS: Routines varied widely in terms of administration routes, cannabinoid content, and use timing. Overall, 18.8%, 36.2%, and 45% used non-inhalation, inhalation, and non-inhalation + inhalation routes, respectively. Those who used inhalation routes were younger (mean age 46.5 [inhalation] and 49.2 [non-inhalation + inhalation] vs. 56.3 [inhalation], F=36.1, p<0.001), while a higher proportion of those who used non-inhalation routes were female (72.5% non-inhalation vs. 48.3% inhalation and 65.3% non-inhalation + inhalation, X2=59.6, p<0.001). THC-rich products were typically used at night, while CBD-rich products were more often used during the day. While all participants reported similarly decreased pain, participants using non-inhalation + inhalation administration routes reported larger improvements in health than the non-inhalation (mean difference = 0.32, 95% CI: 0.07-0.37, p<0.001) and inhalation subgroups (mean difference = 0.22, 95% CI: 0.07-0.37, p=0.001). Similarly, the non-inhalation + inhalation group had significantly more medication substitutions than those using non-inhalation (mean difference = 0.62, 95% CI: 0.33-0.90, p<0.001) and inhalation administration routes (mean difference = 0.45, 95% CI: 0.22-0.69, p<0.001), respectively. CONCLUSIONS: Subgrouping medical cannabis patients based on administration route profile may provide useful categories for future studies examining the risks and benefits of medical cannabis.

Communication between healthcare providers and medical cannabis patients regarding referral and medication substitution.

BACKGROUND: People report using cannabis as a substitute for prescription medications but may be doing so without the knowledge of their primary health care providers (PCPs). This lack of integration creates serious concerns, e.g., using cannabis to treat medical conditions that have established treatment options. METHODS: We conducted an anonymous, cross-sectional online survey among patrons of a medical cannabis dispensary in Michigan (n = 275) to examine aspects of their relationship with their PCP and their perceptions of PCP knowledge related to cannabis. RESULTS: Overall, 64% of participants initiated medical cannabis use based on their own experiences vs. 24% citing advice from their PCP. Although 80% reported that their PCP knew they currently used medical cannabis, 41% reported that their PCP had not always known. Only 14% obtained their medical cannabis authorization from their PCP. Only 18% of participants rated their PCP's knowledge about medical cannabis as very good or excellent and only 21% were very or completely confident in their PCP's ability to integrate medical cannabis into their treatment. Although 86% had substituted cannabis for pharmaceutical medications, 69% (n = 134) of those who substituted reported some gap in their PCP's knowledge of their substitution, and 44% (n = 86) reported that their PCP was currently unaware of their substitution. CONCLUSIONS: Patients frequently substitute cannabis for prescription drugs, often without PCP knowledge. Although most participants disclosed cannabis use to their PCP, their perceptions of PCP knowledge ranged widely and many obtained medical cannabis licensure from an outside physician. Our results highlight the need for standardized physician education around appropriate medical cannabis use.

High-Frequency Medical Cannabis Use Is Associated With Worse Pain Among Individuals With Chronic Pain.

Cannabis is widely used for chronic pain. However, there is some evidence of an inverse dose-response relationship between cannabis effects and pain relief that may negatively affect analgesic outcomes. In this cross-sectional survey, we examined whether daily cannabis use frequency was associated with pain severity and interference, quality of life measures relevant to pain (eg, anxiety and depressive symptoms), and cannabis use preferences (administration routes and cannabinoid ratio). Our analysis included 989 adults who used cannabis every day for chronic pain. Participant use was designated as light, moderate, and heavy (1-2, 3-4, and 5 or more cannabis uses per day, respectively). The sample was also subgrouped by self-reported medical-only use (designated MED, n = 531, 54%) versus medical use concomitant with a past-year history of recreational use (designated MEDREC, n = 458, 46%). In the whole sample, increased frequency of use was significantly associated with worse pain intensity and interference, and worse negative affect, although high-frequency users also reported improved positive affect. Subgroup analyses showed that these effects were driven by MED participants. Heavy MED participant consumption patterns showed greater preference for smoking, vaporizing, and high tetrahydrocannabinol products. In contrast, light MED participants had greater preference for tinctures and high cannabidiol products. Selection bias, our focus on chronic pain, and our cross-sectional design likely limit the generalizability of our results. Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as lower risk cannabis use behaviors among MED participants. Future longitudinal studies are needed to examine how high frequency of cannabis use interacts with potential therapeutic benefits. PERSPECTIVE: Our findings suggest that lower daily cannabis use frequency is associated with better clinical profile as well as safer use behaviors (eg, preference for cannabidiol and noninhalation administration routes). These trends highlight the need for developing cannabis use guidelines for clinicians to better protect patients using cannabis.

Cannabis Use Preferences and Decision-making Among a Cross-sectional Cohort of Medical Cannabis Patients with Chronic Pain.

Cannabis is commonly used to manage chronic pain, but cannabis use patterns among individuals with chronic pain, has not been well-characterized. We report cannabinoid, administration route, and product selection preferences among medical cannabis users with chronic pain from an ongoing, online survey. We also examined whether these preferences are affected by differences in sex, intentions behind use (medical only [MED] vs medical + recreational [MEDREC]), and experience with cannabis (novice: <1 year vs experienced: ≥1 year). The survey was completed by 1,321 participants (59% female) 76.5% of whom used cannabis every day. 93.4% used 2 or more administration routes and 72.5% used 3 or more. Female, MED, and novice users were less likely to smoke or vaporize (all P < .0001), but more likely to rank edibles, tinctures, and topicals as a first-choice administration route than their counterparts. Female and MED users also preferred low THC: high cannabidiol ratios significantly more than their counterparts. Overall, only 2.6% of participants selected cannabis products with input from a medical professional, although 54.9% relied on advice from dispensary employees. More male, MEDREC, and experienced users selected products based on factors that reflected greater comfort with cannabis (eg, smell, visual properties, cannabis variety). The wide variability in cannabis use among these different groups indicates the need for further research to investigate how specific use routines relate to clinical outcomes. PERSPECTIVE: Medical cannabis users with chronic pain show distinct differences in cannabinoid preferences and administration associated with user sex, intentions behind use, and experience with cannabis. This article highlights the wide variability in cannabis preferences among medical cannabis users with chronic pain, which may be relevant for clinical outcomes.

Pills to Pot: Observational Analyses of Cannabis Substitution Among Medical Cannabis Users With Chronic Pain.

Chronic pain is common, costly, and challenging to treat. Many individuals with chronic pain have turned to cannabis as an alternative form of pain management. We report results from an ongoing, online survey of medical cannabis users with chronic pain nationwide about how cannabis affects pain management, health, and pain medication use. We also examined whether and how these parameters were affected by concomitant recreational use, and duration of use (novice: <1 year vs experienced: ≥1 year). There were 1,321 participants (59% female, 54% ≥50 years old) who completed the survey. Consistent with other observational studies, approximately 80% reported substituting cannabis for traditional pain medications (53% for opioids, 22% for benzodiazepines), citing fewer side effects and better symptom management as their rationale for doing so. Medical-only users were older (52 vs 47 years old; P < .0001), less likely to drink alcohol (66% vs 79%, P < .0001), and more likely to be currently taking opioids (21% vs 11%, P < .0001) than users with a combined recreational and medical history. Compared with novice users, experienced users were more likely to be male (64% vs 58%; P < .0001), take no concomitant pain medications (43% vs 30%), and report improved health (74% vs 67%; P = .004) with use. Given that chronic pain is the most common reason for obtaining a medical cannabis license, these results highlight clinically important differences among the changing population of medical cannabis users. More research is needed to better understand effective pain management regimens for medical cannabis users. Perspective: This article presents results that confirm previous clinical studies suggesting that cannabis may be an effective analgesic and potential opioid substitute. Participants reported improved pain, health, and fewer side effects as rationale for substituting. This article highlights how use duration and intentions for use affect reported treatment and substitution effects.

Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain.

UNLABELLED: Opioids are commonly used to treat patients with chronic pain (CP), though there is little evidence that they are effective for long term CP treatment. Previous studies reported strong associations between passage of medical cannabis laws and decrease in opioid overdose statewide. Our aim was to examine whether using medical cannabis for CP changed individual patterns of opioid use. Using an online questionnaire, we conducted a cross-sectional retrospective survey of 244 medical cannabis patients with CP who patronized a medical cannabis dispensary in Michigan between November 2013 and February 2015. Data collected included demographic information, changes in opioid use, quality of life, medication classes used, and medication side effects before and after initiation of cannabis usage. Among study participants, medical cannabis use was associated with a 64% decrease in opioid use (n = 118), decreased number and side effects of medications, and an improved quality of life (45%). This study suggests that many CP patients are essentially substituting medical cannabis for opioids and other medications for CP treatment, and finding the benefit and side effect profile of cannabis to be greater than these other classes of medications. More research is needed to validate this finding. PERSPECTIVE: This article suggests that using medical cannabis for CP treatment may benefit some CP patients. The reported improvement in quality of life, better side effect profile, and decreased opioid use should be confirmed by rigorous, longitudinal studies that also assess how CP patients use medical cannabis for pain management.

Interactions of oversulfated chondroitin sulfate (OSCS) from different sources with unfractionated heparin.

In 2008, oversulfated chondroitin sulfate (OSCS) was identified as the main contaminant in recalled heparin. Oversulfated chondroitin sulfate can be prepared from bovine (B), porcine (P), shark (Sh), or skate (S) origin and may produce changes in the antithrombotic, bleeding, and hemodynamic profile of heparins. This study examines the interactions of various OSCSs on heparin in animal models of thrombosis and bleeding, as well as on the anticoagulant and antiprotease effects in in vitro assays. Mixtures of 70% unfractionated heparin (UFH) with 30% OSCS from different sources were tested. In the in vitro activated partial thromboplastin time (aPTT) assay, all contaminant mixtures showed a decrease in clotting times. In addition, a significant increase in bleeding time compared to the control (UFH/saline) was observed. In the thrombosis model, no significant differences were observed. The OSCSs significantly increased anti-Xa activity in ex vivo blood samples. These results indicate that various sources of OSCS affect the hemostatic properties of heparin.

A comparison of the pharmacodynamic behavior of branded and biosimilar enoxaparin in primates.

Pharmacodynamic behavior of branded and biosimilar enoxaparin was compared in a crossover study in primates. Blood samples collected at baseline and at 1, 4, 6, and 28 hours post-subcutaneous administration of Lovenox or Fibrinox were evaluated using clot-based and amidolytic assays. Anti-Xa levels following Fibrinox and Lovenox administration were not different. Anti-IIa levels were significantly higher in Lovenox-treated animals 1 to 6 hours post-administration. Higher drug levels were measured by Heptest in Fibrinox-treated animals from 4 to 6 hours. Pharmacokinetic differences were not observed using anti-Xa or Heptest assays. The area under the curve (anti-IIa) following Lovenox treatment was significantly larger than following Fibrinox treatment. When drug levels (anti-IIa) were plotted against anti-Xa or Heptest drug levels, a hysteretic relationship which was distinct for Fibrinox- and Lovenox-treated primates was observed suggesting a lack of bioequivalence for the low-molecular-weight heparin tested. In vivo behavior is an important consideration for defining pharmacoequivalence of complex biologic drugs.

Upregulation of inflammatory mediators in end-stage renal disease as measured using biochip array technology.

Systemic vascular changes contribute to both the pathogenesis and thrombotic comorbidities of end-stage renal disease (ESRD). This study aims to profile various biomarkers and better understand their role in the pathogenesis of ESRD. Plasma samples from 49 patients with ESRD and 56 control individuals were analyzed for markers for inflammation, specifically C-reactive protein (CRP), tumor necrosis factor receptor 1 (TNFR1), neutrophil gelatinase-associated lipocalin (NGAL); thrombomodulin (TM); neuron-specific enolase (NSE), and thrombosis-D-dimer (DD). Compared to controls, all markers studied showed a statistically significant upregulation in patients with ESRD. These results indicate a polypathologic process in patients with ESRD, leading to cardiovascular and cerebrovascular events. However, the clinical significance of previously untested markers, such as TNFR1, NGAL, and NSE, still needs to be further explored. This study further validates the role of endothelial damage and endogenous thrombotic processes in ESRD as evidenced by the increased levels of TM and DD.

Assessment of HIT antibody complex in hip fracture patients receiving enoxaparin or unfractionated heparin.

Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants represent a standard of care in preventing postoperative thrombotic complications following surgical fixation. We asked whether levels of antibody to heparin-platelet factor 4 (PF4) complex were differentially present in unfractionated heparin (UFH) versus Enoxaparin, following hip fracture and whether one particular subtype of antibodies was more prevalent. Plasma samples from elderly patients sustaining a hip fracture treated with either enoxaparin or UFH were collected pre- and postoperatively and analyzed using enzyme-linked immunosorbent assay (ELISA) sandwich method for the prevalence of antiheparin-PF4 antibodies and later subtyped. The prevalence of antiheparin-PF4 antibodies was higher in the UFH group especially on postoperative day 7. Patients treated with UFH showed a greater prevalence of antiheparin-PF4 antibodies and a greater prevalence of immunoglobulin G (IgG) subtype. Heparin and enoxaparin are capable of generating heparin-induced thrombocytopenia (HIT) antibodies in elderly patients undergoing orthopedic surgery but perhaps not to the same extent. When comparing low-molecular-weight heparin (LMWH) with UFH, the incidence of new antiheparin-PF4 antibody production is higher in patients treated with UFH.

In vivo neutralization of unfractionated heparin and low-molecular-weight heparin by a novel salicylamide derivative.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are widely used anticoagulants for surgical and interventional use. Currently, the anticoagulant and bleeding effects of heparin are neutralized by protamine sulfate. There are several problems associated with the use of protamine sulfate, including allergic reactions, cardiovascular effects, heparin rebound, and incomplete neutralization of LMWHs. The objective of this investigation is to characterize the effectiveness of a novel salicylamide-derived heparin antagonist, PMX 60056, in neutralizing the antithrombotic and bleeding effects of UFH and LMWHs. Animals were first anticoagulated using an intravenous injection of UFH or LMWH followed by protamine sulfate or PMX 60056. Established animal models of hemorrhage (rat-tail transection) and thrombosis (jugular vein clamping) were then performed. Blood samples were collected for ex vivo analysis using activated partial thromboplastin time (aPTT), anti-Xa, and anti-IIa assays. We demonstrate that PMX 60056 neutralized the antithrombotic, anticoagulant, and bleeding effects of heparins as effectively as protamine sulfate and may be slightly more efficacious against LMWHs. These results suggest that PMX 60056 may provide an improved approach for the neutralization of UFH and LMWHs.

Inflammatory biomarker profiling in elderly patients with acute hip fracture treated with heparins.

Hip fracture is common in the elderly patients with associated high risk of venous thromboembolic complications. Pathogenic activation results in the generation of various surrogate markers in plasma. This study is designed to identify unique biomarkers in elderly patients with hip fracture using protein chip array enzyme-linked immunosorbent assay (ELISA) methods. Plasma from a randomized hip fracture study (PK-532; n = 341) treated with either enoxaparin (40 mg once daily) or unfractionated heparin (UFH; 5000 IU twice daily) were collected prior to and at 1, 3, 5, and 7 days. A total of 52 samples were analyzed using proteomic surface-enhanced laser desorption/ ionization-time of flight (SELDI-TOF) mass spectrometry to identify unique biomarkers in the molecular weight range of 0 to 150 kd. Twenty-nine healthy volunteer's and pooled plasma from total hip replacement/total knee replacement patients with a unique biomarker at 11.9 kd were used as quality controls. In the 29 healthy individuals, the biomarker profile did not reveal the presence of any unique peak in comparison to the reference normal human plasma (NHP). Plasma obtained prior to surgery exhibits unique biomarkers in 4 of 52 (7.6%) of the samples. On day 1 postoperatively, 41 of 51 (80.3%) showed a distinct peak at 11.9 kd. On day 3, 43 of 49 (87.8%) patients showed the presence of this biomarker most often at its strongest intensity. In all, 22 of 44 (50%) showed this biomarker on day 5 and 4 of 23 (17.9%) on day 7. C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and serum amyloid A were also increased after surgery. Tissue factor pathway inhibitor (TFPI) antigen levels were increased due to the treatment modalities.

Relative purity of different bovine thrombin preparations.

The aim of this study was to compare the relative purity of bovine crude thrombin and its purified forms, namely, thrombin 4A and thrombin 4B (the products of King Pharma, Middleton, Wisconsin) by virtue of the detection of bovine prothrombin-related antigens in these preparations. Bovine prothrombin was administered intravenously to 3 individual rabbits on days 0, 21, 42, 91, 123, and 151 using standard immunologic method. Blood was drawn from each rabbit on days 30, 50, 105, 137, and 165, and the pooled antisera from 3 rabbits were purified to isolate immunoglobulin G (IgG) using protein G affinity columns. Using Western blotting method, serially diluted bovine crude thrombin, thrombin 4A, and 4B preparations were probed using the prothrombin IgGs obtained from each time point to explore prothrombin-related antigens in these preparations. The results revealed that compared with the prothrombin IgG collected on day 30, the IgGs collected on days 50 to 165 showed a time-dependent increase in their ability to detect the prothrombin-related antigens in 3 bovine thrombin preparations studied. The lowest amount of crude thrombin, thrombin 4A, and 4B preparations that prothrombin IgG could detect was 0.125, 10, and 20 U, respectively. The rank order of the number of immunoreactive bands detectable in 3 bovine thrombin preparations probed by the prothrombin IgGs collected from any given time point was always the same: crude thrombin > thrombin 4A > thrombin 4B. The results indicate that thrombin 4B preparation contains the least amount of antigens detectable by prothrombin IgG, suggesting that relatively thrombin 4B represents the most purified thrombin preparation among the 3 thrombin preparations studied.

Comparative anticoagulant and platelet modulatory effects of enoxaparin and sulodexide.

Sulodexide represents a novel antithrombotic agent with multiple sites of action on blood coagulation and vascular processes. The purpose of this study was to compare sulodexide and enoxaparin on anticoagulant effects, tissue factor (TF)-induced activation of platelets, inhibition of microparticle generation and to investigate their effect on heparin-induced platelet aggregation (HIPA). Sulodexide was compared with enoxaparin at equigravimetric concentrations. When compared to enoxaparin, sulodexide produced a stronger anticoagulant effect in the prothrombin time (PT), activated partial thromboplastin time (APTT), Heptest, and thrombin time (TT) assays. In addition, sulodexide had a stronger inhibitory effect on TF-mediated microparticle generation (IC(50) = 2.8 microg/ mL), P-selectin expression (IC(50) = 4.8 microg/ml), and platelet aggregate formation (IC(50) = 8.5 microg/mL) compared to higher IC(50) values with enoxaparin. Sulodexide and enoxaparin exhibited a similar effect on heparin-induced thrombocytopenia (HIT) antibody-mediated platelet activation HIPA assays. These results suggest that sulodexide is a relatively stronger anticoagulant agent than enoxaparin. Sulodexide is subcutaneously absorbed. Its ability to inhibit TF-mediated platelet activation may contribute to the observed therapeutic effects of sulodexide in microvascular vasculopathy such as diabetic nephropathy. These results also suggest that inhibition of TF activation of platelets by sulodexide may be independent of its anticoagulant effects. These results warrant further investigation of sulodexide in additional preclinical and clinical studies.

Increased prevalence of antiheparin platelet factor 4 antibodies in patients may be due to contaminated heparin.

During the period of November 2007 to January 2008, an increased prevalence of adverse reactions to heparin was noted. These adverse events have been attributed to the presence of purposeful contaminant, oversulfated chondroitin sulfate (OSCS) from April 2007 to May 2008. An analysis of dialysis patients' plasma obtained in 2006 and 2007 consistently had a low (5%) prevalence of AHPF4 antibodies. Blood samples from 78 patients on maintenance hemodialysis, who were potentially exposed to OSCS-contaminated heparin, were analyzed for the presence of all AHPF4 antibodies using a commercially available ELISA kit from GTI. Although there was no change in the platelet count of these patients, 15 of 78 patients (19.2%) studied had an increased prevalence of AHPF4 antibodies. Subtyping of the all platelet factor 4 (PF4) antibodies documented showed a higher prevalence of immunoglobulin G antibodies as compared to their previously determined antibodies. These observations suggest that the OSCS contaminant in the recalled heparin triggers an immunogenic response not seen with OSCS-contaminated free heparin.

Cortical connections of the second somatosensory area and the parietal ventral area in macaque monkeys.

To gain insight into how cortical fields process somatic inputs and ultimately contribute to complex abilities such as tactile object perception, we examined the pattern of connections of two areas in the lateral sulcus of macaque monkeys: the second somatosensory area (S2), and the parietal ventral area (PV). Neuroanatomical tracers were injected into electrophysiologically and/or architectonically defined locations, and labeled cell bodies were identified in cortex ipsilateral and contralateral to the injection site. Transported tracer was related to architectonically defined boundaries so that the full complement of connections of S2 and PV could be appreciated. Our results indicate that S2 is densely interconnected with the primary somatosensory area (3b), PV, and area 7b of the ipsilateral hemisphere, and with S2, 7b, and 3b in the opposite hemisphere. PV is interconnected with areas 3b and 7b, with the parietal rostroventral area, premotor cortex, posterior parietal cortex, and with the medial auditory belt areas. Contralateral connections were restricted to PV in the opposite hemisphere. These data indicate that S2 and PV have unique and overlapping patterns of connections, and that they comprise part of a network that processes both cutaneous and proprioceptive inputs necessary for tactile discrimination and recognition. Although more data are needed, these patterns of interconnections of cortical fields and thalamic nuclei suggest that the somatosensory system may not be segregated into two separate streams of information processing, as has been hypothesized for the visual system. Rather, some fields may be involved in a variety of functions that require motor and sensory integration.