Experiences and Perceptions of Medical Cannabis among People Living with Chronic Pain and Community Pharmacists: A Qualitative Study in Canada.

Background: The use of cannabis to treat chronic pain is under debate despite high expectations from patients. Qualitative data obtained by exploring both patients' and health professionals' perspectives are scarce. Aims: This study aimed to understand the experiences and perceptions of people living with chronic pain and community pharmacists regarding the role of cannabis in chronic pain treatment in the Canadian context where both medical and recreational cannabis are legal. Methods: We conducted 12 online focus groups (July 2020-February 2021) with 26 patients and 19 community pharmacists using semistructured discussion guides. All discussions were audio recorded and transcribed verbatim were analyzed using a reflexive thematic approach. Results: We developed three themes related to patients' perspectives and three themes related to pharmacists' perspectives. Patients' perspectives included (1) cannabis as an alternative to other pain medications, (2) a new treatment with potential health-related risks, and (3) a therapy rather than a recreational drug. Pharmacists' perspectives included (1) challenges in monitoring drug interactions with cannabis in the context of scarce research data, (2) informing and treating patients self-medicating with cannabis amid its growing popularity, and (3) financial costs and legal constraints for patients. Conclusions: This study highlights patients' and pharmacists' urgent need for reliable information regarding the benefits and risks of cannabis. Training tailored to pharmacists' needs and evidence-based information for patients should be developed to support pharmacists' practice, improve patients' experiences, and promote safe cannabis use.

Contexte: L'utilisation du cannabis pour traiter la douleur chronique fait l'objet d'un débat, malgré les fortes attentes des patients. Les données qualitatives issues de l'exploration des perspectives à la fois des patients et des professionnels de la santé, demeurent rares.Objectifs: Cette étude visait à comprendre les expériences et les perceptions des personnes vivant avec une douleur chronique et des pharmaciens communautaires concernant le rôle du cannabis dans le traitement de la douleur chronique dans le contexte canadien, où le cannabis médical et récréatif est légal.Méthodes: Nous avons mené 12 groupes de discussion en ligne entre juillet 2020 et février 2021, réunissant 26 patients et 19 pharmaciens communautaires, à l'aide de guides de discussion semi-structurés. Toutes les discussions ont été enregistrées et transcrites mot à mot, puis analysées à l'aide d'une approche thématique réflexive.Résultats: Nous avons développé trois thèmes liés aux perspectives des patients et trois thèmes liés aux perspectives des pharmaciens. Le point de vue des patients incluait (1) le cannabis comme option de rechange à d'autres médicaments contre la douleur, (2) un nouveau traitement avec des risques potentiels pour la santé, et (3) un traitement plutôt qu'une drogue récréative. Le point de vue des pharmaciens portait sur (1) les défis liés à la surveillance des interactions médicamenteuses avec le cannabis dans le contexte de la rareté des données de recherche, (2) l'information et le traitement des patients qui s'auto-médicamentent avec du cannabis dans un contexte de popularité croissante, et (3) les coûts financiers et les contraintes légales pour les patients.Conclusions: Cette étude met en évidence le besoin urgent des patients et des pharmaciens de disposer d'informations fiables sur les avantages et les risques du cannabis. Une formation adaptée aux besoins des pharmaciens et des informations fondées sur des données probantes pour les patients devraient être développées pour soutenir la pratique des pharmaciens, améliorer l'expérience des patients et promouvoir une utilisation sûre du cannabis.

Swallowing the pill of adverse effects: A qualitative study of patients' and pharmacists' experiences and decision-making regarding the adverse effects of chronic pain medications.

INTRODUCTION: Pharmacological treatments of chronic pain can lead to numerous and sometimes serious adverse effects. Drawing on a social science approach to chronic illness, this study aimed to understand the experiences of people living with chronic pain and community pharmacists regarding the definition, prevention and management of analgesic adverse effects. METHODS: This qualitative study proceeded through 12 online focus groups (FGs) with people living with chronic pain (n = 26) and community pharmacists (n = 19), conducted between July 2020 and February 2021 in the province of Quebec, Canada. The semistructured discussion guides covered participants' definitions of adverse effects and decision-making regarding their prevention and management. Discussions were audio-recorded, transcribed verbatim and analysed using grounded theory. RESULTS: Both people with chronic pain and pharmacists provided varying definitions of analgesic adverse effects depending on patients' social and clinical characteristics. Present quality of life and serious long-term risks related to treatment were described as key dimensions influencing adverse effect appraisal. Dilemmas and discrepancies occurred between patients and pharmacists when choosing to prioritize pain relief or adverse effect prevention. Some patients lacked information about their medications and wanted to be more involved in decisions, while many pharmacists were concerned by patients' self-management of adverse effects. Preventing opioid-related overdoses often led pharmacists to policing practices. Despite most pharmacists wishing they could have a key role in the management of pain and adverse effects face organizational and financial barriers. CONCLUSION: Defining, preventing and managing adverse effects in the treatment of chronic pain requires a person-centred approach and shared decision-making. Clinical training improvements and healthcare organization changes are needed to support pharmacists in providing patients with community-based follow-up and reliable information about the adverse effects of chronic pain treatments. PATIENT OR PUBLIC CONTRIBUTION: A person with lived experience of chronic pain was involved as a coinvestigator in the study. He contributed to shaping the study design and objectives, including major methodological decisions such as the choice of pharmacists as the most appropriate professionals to investigate. In addition, 26 individuals with chronic pain shared their experiences extensively during the FGs.

The Quebec Low Back Pain Study: a protocol for an innovative 2-tier provincial cohort.

INTRODUCTION: The neurobiological mechanisms underlying recovery from or persistence of low back pain (LBP) remain misunderstood, limiting progress toward effective management. We have developed an innovative two-tier design to study the transition from acute to chronic LBP. The objective of the first tier is to create a provincial web-based infrastructure to recruit and monitor the trajectory of individuals with acute LBP. The objective of the second tier is to fuel hypothesis-driven satellite data collection centers with specialized expertise to study the role of biomechanical, epigenetic, genetic, neuroanatomical, ontological, physiological, psychological, and socioeconomic factors in LBP chronicity. METHODS: This article describes the first tier of the protocol: establishment of the Core Dataset and Cohort. Adults with acute LBP will be recruited through networks, media, and health care settings. A web-based interface will be used to collect self-reported variables at baseline and at 3, 6, 12, and 24 months. Acute LBP will be defined according to the Dionne 2008 consensus. Measurements will include the Canadian minimum data set for chronic LBP research, DN4 for neuropathic pain, comorbidities, EQ-5D-5L for quality of life, and linkage with provincial medico-administrative databases. The primary outcome will be the transition to chronic LBP, as defined by Deyo 2014. Secondary outcomes include health care resource utilization, disability, sick leave, mood, and quality of life. PERSPECTIVE: This study brings together diverse research expertise to investigate the transition from acute to chronic LBP, characterize the progression to recovery or chronicity, and identify patterns associated with that progression.

In ovo vaccination using Eimeria profilin and Clostridium perfringens NetB proteins in Montanide IMS adjuvant increases protective immunity against experimentally-induced necrotic enteritis.

OBJECTIVE: The effects of vaccinating 18-day-old chicken embryos with the combination of recombinant Eimeria profilin plus Clostridium perfringens (C. perfringens) NetB proteins mixed in the Montanide IMS adjuvant on the chicken immune response to necrotic enteritis (NE) were investigated using an Eimeria maxima (E. maxima)/C. perfringens co-infection NE disease model that we previously developed. METHODS: Eighteen-day-old broiler embryos were injected with 100 µL of phosphate-buffered saline, profilin, profilin plus necrotic enteritis B-like (NetB), profilin plus NetB/Montanide adjuvant (IMS 106), and profilin plus Net-B/Montanide adjuvant (IMS 101). After post-hatch birds were challenged with our NE experimental disease model, body weights, intestinal lesions, serum antibody levels to NetB, and proinflammatory cytokine and chemokine mRNA levels in intestinal intraepithelial lymphocytes were measured. RESULTS: Chickens in ovo vaccinated with recombinant profilin plus NetB proteins/IMS106 and recombinant profilin plus NetB proteins/IMS101 showed significantly increased body weight gains and reduced gut damages compared with the profilin-only group, respectively. Greater antibody response to NetB toxin were observed in the profilin plus NetB/IMS 106, and profilin plus NetB/IMS 101 groups compared with the other three vaccine/adjuvant groups. Finally, diminished levels of transcripts encoding for proinflammatory cytokines such as lipopolysaccharide-induced tumor necrosis factor-α factor, tumor necrosis factor superfamily 15, and interleukin-8 were observed in the intestinal lymphocytes of chickens in ovo injected with profilin plus NetB toxin in combination with IMS 106, and profilin plus NetB toxin in combination with IMS 101 compared with profilin protein alone bird. CONCLUSION: These results suggest that the Montanide IMS adjuvants potentiate host immunity to experimentally-induced avian NE when administered in ovo in conjunction with the profilin and NetB proteins, and may reduce disease pathology by attenuating the expression of proinflammatory cytokines and chemokines implicated in disease pathogenesis.

Evaluation of Montanide™ ISA 71 VG adjuvant during profilin vaccination against experimental coccidiosis.

Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus Montanide™ ISA 70 VG (ISA 70) or Montanide™ ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray hybridizations were performed to ascertain global transcriptome changes induced by profilin/ISA 70 vs. profilin alone and by profilin/ISA 71 vs. profilin alone. While immunization with profilin/ISA 70 vs. profilin alone altered the levels of more total transcripts compared with profilin/ISA 71 vs. profilin alone (509 vs. 296), the latter was associated with a greater number of unique biological functions, and a larger number of genes within these functions, compared with the former. Further, canonical pathway analysis identified 10 pathways that were associated with genes encoding the altered transcripts in animals immunized with profilin/ISA 71 vs. profilin alone, compared with only 2 pathways in profilin/ISA 70 vs. profilin alone. Therefore, ISA 71 was selected as a candidate adjuvant in conjunction with profilin vaccination for in vivo disease protection studies. Vaccination with profilin/ISA 71 was associated with greater body weight gain following E. acervulina infection, and decreased parasite fecal shedding after E. maxima infection, compared with profilin alone. Anti-profilin antibody levels were higher in sera of E. maxima- and E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. Finally, the levels of transcripts encoding interferon-γ, interleukin (IL)-2, IL-10, and IL-17A were increased in intestinal lymphocytes from E. acervulina-, E. maxima-, and/or E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. None of these effects were seen in chickens injected with ISA 71 alone indicating that the adjuvant was not conferring non-specific immune stimulation. These results suggest that profilin plus ISA 71 augments protective immunity against selective Eimeria species in chickens.

Vaccination with Clostridium perfringens recombinant proteins in combination with Montanide™ ISA 71 VG adjuvant increases protection against experimental necrotic enteritis in commercial broiler chickens.

This study was performed to compare four Clostridium perfringens recombinant proteins as vaccine candidates using the Montanide™ ISA 71 VG adjuvant in an experimental model of necrotic enteritis. Broiler chickens were immunized subcutaneously with purified clostridial recombinant NetB toxin, pyruvate: ferredoxin oxidoreductase (PFO), α-toxin, or elongation factor-Tu (EF-Tu), or with vehicle control, in conjunction with ISA 71 VG, and intestinal lesion scores, body weight gains, NetB toxin and PFO antibody levels, and proinflammatory cytokine and chemokine levels were measured as outcomes of protection following oral co-infection with C. perfringens and Eimeria maxima. Birds immunized with all recombinant proteins plus ISA 71 VG showed significantly reduced gut lesions compared with the ISA 71 VG-only group. Birds immunized with NetB toxin or PFO plus ISA 71 VG exhibited significantly increased body weight gains compared with the ISA 71 VG alone group. Greater NetB toxin antibody titers were observed in the NetB/ISA 71 VG group, and greater PFO antibody titers were evident in the PFO/ISA 71 VG group, each compared with the other three vaccine/adjuvant groups. Finally, decreased levels of gene transcripts encoding interleukin-8, tumor necrosis factor superfamily 15, and LPS-induced TNF-α factor were observed in the intestinal lymphocytes of chickens immunized with NetB toxin, PFO, α-toxin, and/or EF-Tu in the presence of ISA 71 VG compared with ISA 71 VG alone. All parameters evaluated were equal in co-infected chickens given ISA 71 VG alone compared with infected/adjuvant-free birds, indicating that the adjuvant itself did not have a disease protective effect. These results suggest that vaccination with clostridial recombinant proteins, particularly NetB toxin or PFO, in combination with ISA 71 VG enhances protective immunity against experimental necrotic enteritis in broiler chickens.

Efficacy of intranasal and spray delivery of adjuvanted live vaccine against infectious bronchitis virus in experimentally infected poultry.

Live vaccines are widely used in the avian industry. Such vaccines can be either injected or delivered on animal mucosa and are usually not adjuvanted. In this study we show that live vaccines efficacy can be improved by formulation with adjuvants in a model of mucosal delivery of live infectious bronchitis vaccine in chicken. Three adjuvant technologies have been tested using intranasal and spray delivery methods to poultry. Those technologies are water in oil in water emulsion, nanoparticles and polymer adjuvants. Intranasal delivery of polymer and nanoparticles adjuvanted live vaccines improved significantly the antibody titer and protection to challenge observed compared to a commercial non-adjuvanted reference. Moreover, spray delivery of the polymer adjuvanted vaccine showed a significantly higher protection compared to the non-adjuvanted reference. Our data demonstrates that the use of MontanideTM adjuvants in the formulation of live poultry vaccines for mucosal delivery can confer to vaccinated animals a significantly improved protection against pathogens.

Load reduction in live PRRS vaccines using oil and polymer adjuvants.

PRRSV live vaccines are widely used in pig farming practice and are usually not adjuvanted. For safety issues, it would be useful to reduce the antigenic load of such vaccines while preserving their efficacy. In this study we show that the addition of polymer or oil adjuvants in a PRRS live vaccine enhanced the protection to challenge of vaccinated animals compared to a non-adjuvanted commercial reference. Moreover, for both types of adjuvants, despite lower antibody titers, the protection to challenge given by the adjuvanted vaccine containing only 50% of the antigen load was equivalent to the protection given by the non-adjuvanted vaccine. These results demonstrate that the addition of relevant adjuvants can enhance the efficacy of the protection conferred to animals by live vaccines.

Mucosal immunity against Eimeria acervulina infection in broiler chickens following oral immunization with profilin in Montanide™ adjuvants.

The present study was conducted to compare aqueous nanoparticle-based Montanide™ IMS 1313 N VG PR (IMS 1313) and oil-based ISA 71 VG (ISA71) adjuvants in combination with an Eimeria subunit protein vaccine on protection against avian coccidiosis. Male broiler chicks were vaccinated twice with an Eimeria recombinant profilin protein alone or in conjunction with IMS 1313 or ISA 71 prior to infection with live, sporulated Eimeria acervulina oocysts. For comparison, chickens were immunized with a commercial live coccidiosis vaccine (Coccivac-B). The following parameters were assessed as measures of protective immunity: body weight gain, fecal oocyst output, profilin-specific intestinal secretary IgA (sIgA) or IgY antibody levels, and percentages of CD4(+), CD8(+), TCR1(+), or TCR2(+) intestinal intraepithelial lymphocytes (IELs). Birds vaccinated with profilin plus ISA 71 had increased body weight gains, equivalent to Coccivac-B vaccination, compared with the profilin-only group. Immunization with profilin plus IMS 1313, or with profilin plus ISA 71, reduced fecal oocysts shedding compared with the profilin-only group. Intestinal sIgA levels were greater in the profilin plus IMS 1313 or ISA 71 groups, and IgY levels were greater in the profilin plus ISA 71 group, compared with profilin alone. Birds vaccinated with profilin plus IMS 1313 or ISA 71 had higher percentages of CD4(+), CD8(+), and TCR1(+), but not TCR2(+), intestinal IELs compared with the profilin-only vaccinated group. Taken together, these results indicate that immunization of chickens with the recombinant profilin subunit vaccine in conjunction with IMS 1313 or ISA 71 adjuvants increases protective immunity against experimental E. acervulina infection.

Montanide IMS 1313 N VG PR nanoparticle adjuvant enhances antigen-specific immune responses to profilin following mucosal vaccination against Eimeria acervulina.

This study investigated protection against Eimeria acervulina (E. acervulina) following vaccination of chickens with an Eimeria recombinant profilin in conjunction with different adjuvants, or by changing the route of administration of the adjuvants. Day-old broilers were immunized twice with profilin emulsified in Montanide IMS 1313 N VG PR adjuvant (oral, nasal, or ocular routes), Montanide ISA 71 VG adjuvant (subcutaneous route), or Freund's adjuvant (subcutaneous route) and orally challenged with virulent E. acervulina parasites. Birds orally immunized with profilin plus IMS 1313 N VG PR, or subcutaneously immunized with profilin plus ISA 71 VG, had increased body weight gains compared with animals nasally or ocularly immunized with profilin plus IMS 1313 N VG PR, or subcutaneously immunized with profilin plus Freund's adjuvant. All adjuvant formulations, except for IMS 1313 N VG PR given by the nasal or ocular routes, decreased fecal parasite excretion and/or reduced intestinal lesions, compared with non-vaccinated and infected controls. Compared with animals vaccinated with profilin plus Freund's adjuvant, chickens immunized with profilin plus IMS 1313 N VG PR or ISA 71 VG showed higher post-infection intestinal levels of profilin-reactive IgY and secretary IgA antibodies. Finally, immunization with profilin in combination with ISA 71 VG was consistently better than profilin plus IMS 1313 N VG PR or Freund's adjuvant for increasing the percentages of CD4(+), CD8(+), BU1(+), TCR1(+), and TCR2(+) intestinal lymphocytes. These results indicate that experimental immunization of chickens with the recombinant profilin subunit vaccine in conjunction with IMS 1313 or ISA 71 VG adjuvants increases protective mucosal immunity against E. acervulina infection.

Montanide™ ISA 71 VG adjuvant enhances antibody and cell-mediated immune responses to profilin subunit antigen vaccination and promotes protection against Eimeria acervulina and Eimeria tenella.

The present study was conducted to investigate the immunoenhancing effects of Montanide™ ISA 71 VG adjuvant on profilin subunit antigen vaccination. Broiler chickens were immunized subcutaneously with a purified Eimeria acervulina recombinant profilin protein, either alone or mixed with ISA 71 VG, and host immune responses were evaluated. After secondary immunization, antigen-specific antibody and T-cell responses were higher in the group which received profilin plus ISA 71 VG compared with the other groups. Furthermore, body weight gains and fecal oocyst shedding were evaluated following oral challenge infection with live E. acervulina or Eimeria tenella oocysts. Vaccination with profilin plus ISA 71 VG reduced oocyst shedding compared with animals immunized with profilin alone. These results demonstrate that the recombinant profilin subunit vaccine, when given in combination with Montanide™ ISA 71 VG, augments protective immunity against E. acervulina and E. tenella.

Immunoenhancing effects of Montanide ISA oil-based adjuvants on recombinant coccidia antigen vaccination against Eimeria acervulina infection.

The current study was conducted to investigate the immunoenhancing effects of Montanide adjuvants on protein subunit vaccination against avian coccidiosis. Broiler chickens were immunized subcutaneously with a purified Eimeria acervulina recombinant profilin protein, either alone or mixed with one of four adjuvants (ISA 70 VG, ISA 71 VG, ISA 201 VG or ISA 206 VG), and body weight gains, fecal oocyst shedding, and humoral and innate immune responses were evaluated following oral challenge infection with live E. acervulina oocysts. Immunization with profilin plus ISA 70 VG or ISA 71 VG increased body weight gains compared with vaccination with profilin alone. Profilin plus ISA 71 VG also reduced fecal oocyst shedding compared with vaccination in the absence of adjuvant. All adjuvants enhanced profilin serum antibody titers. Increased levels of gene transcripts encoding IL-2, IL-10, IL-17A, and IFN-gamma, but decreased levels of IL-15 mRNAs, were seen in intestinal intraepithelial lymphocytes of chickens immunized with profilin plus adjuvants compared with immunization with profilin alone. Finally, increased infiltration of lymphocytes, especially CD8(+) lymphocytes at the site of immunization was observed in birds given profilin plus ISA 71 VG compared with profilin alone. These results demonstrate that vaccination with the E. acervulina profilin subunit vaccine in combination with Montanide adjuvants enhances protective immunity against avian coccidiosis.

The use of oil adjuvants in therapeutic vaccines.

Water in oil emulsions represents one of the new promising generations of adjuvants for immunotherapy. Fifty years ago, incomplete freund adjuvant (IFA) has been used in clinical trials for prophylactic vaccines like poliomyelitis or flu vaccine because of its strong potency. However, even if the quality of the raw materials has been improved in order to avoid secondary reactions, the risk benefit ratio was not favorable to its use for prophylactic vaccines. Moreover, emulsions were highly viscous with a weak stability. The development of new adjuvants concepts like liposomes, oil in water emulsions, bacterial immunostimulating compounds has induced a loss of interest for such formulations. The emergence of immunotherapy treatments for cancer, AIDS or other diseases leads to the re-emergence of these adjuvants, as the risk benefit ratio is more favorable. Then, safety of these adjuvants has been improved by the use of more specific surfactants and refined oils but also by improving their manufacturing process, allowing even sometimes their use in clinical trials for prophylactic vaccines.

Surfactants in vaccine adjuvants: description and perspectives.

Amphiphilic molecules, called surfactants, are made of a lipophilic part linked to a hydrophilic part. These substances have physicochemical properties of self-aggregation, solubilisation or emulsification. Their ability to be attracted at the same time by polar and non-polar compounds forces them to be at the interface. Surfactants most frequently used in vaccines can be of natural or synthetic origin, non-ionic, cationic or amphoteric with a formula weight between 600 and 4000 g/mol. They can be used as adjuvants, solubilisers or stabilisers of emulsions. Physicochemical properties are defined through solubility parameters or solution behaviours and hydrophilic lipophilic balance (HLB). Application properties are assessed through placebo formulations simulating the final use. Synthetic products are preferred to products of natural origin for quality reasons. Development of a new generation of surfactant with precise chemical definition and consistency may generate new candidates for potential vaccine adjuvants.