Cannabinoids and orthopedic surgery: a systematic review of therapeutic studies

Background Recent work has shed light on the potential benefits of cannabinoids for multimodal pain control following orthopedic procedures. The objective of this review was to summarize the available evidence of analgesic and opioid-sparing effects cannabinoids have in orthopedic surgery and identify adverse events associated with their use. Methods A systematic review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines including PubMed, EMBASE, MEDLINE, PsycINFO, and Google Scholar was performed to include all primary, therapeutic studies published on the use of cannabis, and cannabis-derived products in orthopedic surgery. Results The literature review returned 4292 citations. Thirteen publications were found to meet inclusion criteria. Four randomized controlled trials were evaluated while the remaining studies were of quasi-experimental design. Conclusion Research on cannabinoids in orthopedic surgery is mostly of a quasi-experimental nature and is mainly derived from studies where orthopedics was not the primary focus. The overall results demonstrate potential usefulness of cannabinoids as adjunctive analgesics and in mitigating opioid use. However, the current evidence is far from convincing. There is a need to produce rigorous evidence with well-designed randomized controlled trials specific to orthopedic surgery to further establish these effects.

appraising the literature through 2017 [8]. Since this time, there has been evidence attesting to the benefit of cannabinoids on post-operative recovery and reduction in morphine use following orthopedic procedures [9]. Given the current trend of widespread opioid misuse within the USA [10], this potential to limit narcotic use is promising. Legality has continued to expand [1] and the popularity of cannabinoids has increased where 14% of Americans in 2019 used CBD products, most commonly for pain [11]. The objective of this review was to summarize the available evidence of analgesic and opioid-sparing effects cannabinoids have within orthopedic surgery and identify adverse events (AE) associated with their use.

Methods
Guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) and PRISMA checklist of recommended items to include in a systematic review were utilized in the construction of this systematic review [12] (Additional file 1: PRISMA Checklist).

Eligibility criteria
Only primary works of interventional design were considered. Articles combining the therapeutic use of cannabinoids and any subspecialty of orthopedic surgery or conditions common to the field such as fractures, osteoarthritis, and back pain were included. Case reports were excluded, as were non-English and preclinical studies.

Study selection
A title review was performed of all citations found in each database independently. Duplicate citations were removed, and the abstracts were reviewed. The remaining studies underwent full text review, where each was read individually by at least two of the authors. The review process was performed by BJV and ANS. All disputes of inclusion were settled with the senior authors.

Data extraction and synthesis
The following data were gathered: study design, population, intervention, control, analgesic effect, differences in opioid use, and AEs. Management of data was done with an electronic chart in which all extracted data was listed by study and utilized for the writing of the manuscript.

Appraisal of evidence
Evidence of each study was evaluated utilizing the Grading of Recommendations of Assessment, Development, and Evaluation (GRADE) criteria [13] and therapeutic level of evidence was assigned as outlined in the Journal of Bone and Joint Surgery [14]. Bias was assessed with the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) in randomized controlled trials (RCTs); crossover trials were evaluated with the RoB2 tool specific for crossover trials [15]. The Risk of Bias In Non-Randomized Studies-of Interventions (ROBINS-I) [16] tool was used to assess bias in comparative nonrandomized studies. Given the inherent biases found with case series designs, studies without comparative groups were not assessed for bias. Bias was assessed contemporaneously by BJV and ANS.

Results
The search produced a total of 4292 titles, and 13 publications met our inclusion criteria. The process in which these 13 references were obtained is tabulated in the PRISMA flowsheet depicted by Moher and colleagues [12] (Fig. 2).

Intervention
A multiplicity of interventions was used. Oral caplets of cannabinoids were the most common, comprising four studies [9,17,20,25]. Two exclusively utilized the combustion or vaporization of cannabis [23,24]. Liquid oral administration either sublingual or THC/CBD suspension was used in three studies [22,27,28]. One utilized transdermal CBD gel [18], while another used intramuscular levonantradol [19]. Two allowed for patient choice of administration resulting in mixed delivery; most commonly smoked cannabis [21,26]. The dose, frequency, and potency of cannabinoid varied widely and can be seen by study in Table 3.

Control
Six studies had separate control groups. Among RCTs, one study included a positive control of ketoprofen and negative placebo [17], while the remaining three involved only identical placebo as negative control [18][19][20]. Only two of the non-randomized trials involved a parallel control group: one involved subjects characteristically matched to the intervention group [9] and the other had multiple, statistically significant differences among subjects between intervention and control [21]. Information on control groups is further tabulated in Table 3,
One study reported an exacerbation of pain with increased doses of nabilone (2 mg vs. 1 mg) [17], and another found the pain control provided by 2.5 mg of levonantradol was significantly better than 3 mg [19]. A null effect was also reported with increased dosages, 500 mg/day of topical CBD was not associated with significantly increased analgesia vs. 250 mg/day in the setting of knee osteoarthritis [18]. In contrast, the analgesic effect of 10 mg and 15 mg of oral CBD/THC was found superior to 5 mg in the one dose escalation trial [25].

Opioid-sparing effects
Seven studies quantified the effect of cannabinoids upon opioid use [9,[23][24][25][26], including two RCTs [17,20]. Five noted a decrease in opioids administered [9,[23][24][25][26], while both RCTs reported no change [17,20]. In the perioperative setting, no change in morphine equivalents given was found by two [17,20], a reduction of total morphine equivalents given across a hospital stay was found in one [9], and a dose-dependent response in the reduction of rescue analgesia in another [25]. Two studies noted complete cessation of opioid use in the majority of subjects with chronic pain with six [26] to twelve [23] months of cannabinoid use (Table 4).

Discussion
The therapeutic application of cannabinoids is an emerging area of research. While Madden et al. focused on study methodology in their reviews appraising the literature through 2017 [8,29], new studies have since been published [9,18,24,27]. In addition to evaluating these new studies, we sought to narrow the focus of our review to analgesic and opioid-sparing effects of cannabinoids within orthopedic surgery. The importance of investigation into supplemental analgesics is underscored by the current opioid epidemic in the USA, where nearly 10,000,000 people misused prescription opioids [10] and over 40,000 died of overdose in 2018 [30]. Among all opioid prescriptions, 5.8% [31] to 7.7% [32] were written by orthopedic surgeons, indicating that the field is not immune to the growing opioid problem [33]. While useful for post-operative pain, several studies have demonstrated an alarming trend of use long after convalescence from the index surgery [34][35][36], even among opioid-naïve patients [37][38][39]. This trend may be amplified in the future by the projected growth of orthopedic procedures; the number of TKA and THAs are estimated to quadruple from 2010 to 2030 [40]. The neuropharmacology of cannabinoids regarding nociception [41] make them a promising adjunctive analgesic that could potentially mitigate the need for opioids.

Study Adverse events
Beaulieu [17] 2 mg nabilone: increased sedation and pain Xerostomia, nausea, vomiting, respiratory depression, pruritis common but not different between groups Haroutounian et al. [26] Mild-moderate: n = 9 (sedation, heaviness, decreased concentration) Severe: n = 2 (increased transaminases and acute confusion) Hickernell et al. [9] None during length of hospital course (mean 2.   [19]. Indeed, the sexual dimorphism of cannabinoid pharmacology has been discussed [42,43] and a recent review noted differing degrees of analgesia among sexes across nine clinical and preclinical studies [43]. All nine non-RCTs demonstrated a positive analgesic effect. However, these studies were non-randomized and only two had parallel control groups limiting the applicability and generalizability of the findings. The reduction in opioid use was promising; five of seven studies demonstrated reduced opioid consumption with cannabinoid therapy. Holdcroft el al. noted a dosedependent response in the reduction of rescue analgesia in their trial evaluating post-operative pain [25]. Hickernell et al. reported a reduction in perioperative opioid use; however, this was in the setting of a decreased length of stay in their dronabinol group and no significant change in opioid use per day [9]. A sizeable portion of subjects were able to discontinue opioid therapy at six [26] and twelve [23]  There was a lack of standardization among dose, frequency, concentration, and route of administration. Caplets of synthetic THC were studied in doses of 0.5 mg taken once [20], 5 mg twice a day throughout the hospital course following the index procedure [9], and 1 mg or 2 mg taken four times within 24 h [17]. Levonantradol, another synthetic THC derivative, was administered in 1.5 mg, 2 mg, 2.5 mg, and 3 mg aliquots intramuscularly by Jain et al. [19]. Synthetic transdermal CBD was dosed at either 250 mg or 500 mg a day [18]. Natural cannabinoids ranged in concentrations of < 5% [24] to 95% [22] THC and < 1% [28] to 95% [22] CBD. Oral caplets were dosed 5-15 mg [25], sublingual drops 2.5 mg [22], and oral extractions 28 mg [28] to 68.5 mg [27]. All four studies evaluating smoked cannabis varied in median dose ranging from 600 mg [23] to 2500 mg daily [21].
Cannabinoid choice varied among studies and included synthetic and natural THC, CBD, and THC/CBD combinations. Nottcut et al. demonstrated an increased efficacy of THC and THC/CBD in combination over CBD alone [22]. This finding is also supported elsewhere; a RCT evaluating oncogenic pain found THC/ CBD mixtures were more efficacious than placebo and THC alone [44]. The combination of THC and CBD may be useful. Preclinical research has suggested that CBD can mitigate the neuropsychiatric effects produced by THC [45,46]. Synergism among endogenous cannabinoids [47] has led to the speculation of a similar relationship where THC and CBD may augment the effects of one another when administered synchronously in what has been termed the "entourage effect" [48,49].
All but one study [9] found AEs. Ware et al. specifically sought to measure AEs primarily with smoked cannabis, noting decreased pulmonary function as well as increased upper respiratory complaints and infections within their cannabis group over the course of 12 months [21]. Smoking was a common route of administration found in this review and many concerns with the combustion of organic plant material exist. Indeed, the deleterious effects of smoked tobacco are well known [50]. Although less studied, cannabis smoke has been associated with negative sequalae such as lung cancer [51] and lower bone mineral densities among heavy users [52].
Among other routes of administration, Hickernell et al. noted no AEs among 81 patients receiving 5 mg dronabinol [9], while studies evaluating nabilone recorded increased rates of impaired muscle coordination [20] and sedation [17] at 0.5 mg and 2 mg respectively. Other common reported effects include nausea, vomiting, altered mentation, and potential drug interactions [4]. Transdermal CBD products are less known in terms of AEs; Hunter et al. found an increased incidence of headache and application site xerosis with this modality vs. placebo [18]. Due to a severe vasovagal event at 15 mg THC/CBD, Holdcroft et al. ceased recruitment in their study. This same study noted a dose-dependent response in AEs from 5 to 15 mg of oral THC/CBD [25]; however, Jain et al. did not demonstrate a dose related response in AEs from 1.5 to 3 mg IM levonantradol [19]. Neuropsychiatric events were rare, consisting mainly of sedation. Euphoria and hallucinations were reported, but rarely. Overall, cannabinoids were welltolerated within this review; however, this is insufficient evidence to fully evaluate the safety of these compounds. Similarly, the stark differences in route of administration, dose, and actual cannabinoid used underscore the lack of standardization in the use of these compounds and create difficulty in comparing their safety and efficacy across the literature.
Among adverse events, the potential for addiction, chronic dependence, and the resultant socioeconomic effects of employing cannabinoids into orthopedic practice are salient concerns that unfortunately were not assessed within the studies included in this review. However, both the benefits and risks of any therapy must be considered. The ravages of opioid addiction are known, summating in tens of thousands of deaths per year in the USA [30]. The ability of cannabinoids to mitigate this crisis outweighs the negative ramifications in the authors' opinion. Indeed, in states of the USA where cannabinoid use has become legal, there have been decreased rates of opioid prescriptions, opioid abuse, opioid-associated hospital admissions, and overdose mortality rates [53][54][55]. Cannabinoids are mechanistically different than opioids resulting in key differences [41]. Opioids depress respiratory drive [56] and indeed this is the primary mechanism of death in acute overdose [57]. Contrarily, no fatal overdoses have been reported with medical or recreational cannabinoid use; furthermore, the quantity of cannabinoids needed to induce a potentially fatal overdose is many multitudes beyond the therapeutic dose [58,59]. Paradoxically, higher doses of cannabinoids have been reported to cause hyperalgesia [60]. This effect may provide a ceiling to the continual upward titration of dosages. The prolonged use of opioids has been associated with hyperalgesia possibly begetting the need for an ever-increasing dosage to adequately address pain [61]. In contrast, cannabinoids have been shown to not induce hyperalgesia with chronic use [62]. The combination of these factors speaks against chronic dependence upon cannabinoids for pain control.
There are several limitations acknowledged within this review. The dearth of literature existing on cannabinoids in orthopedic surgery left few studies to review. Much of our data was extracted from papers where only a fraction of the subjects underwent orthopedic procedures or had orthopedic conditions. It is impossible to know in these studies what the true impact of cannabinoids was on orthopedic patients given the data of all subjects was combined. The heterogeneity of data and methodology made it impossible to perform a meta-analysis. The overall quality of available data also affects this review, given many studies included are either low to very low in quality and only four RCTs met the inclusion criteria.

Conclusion
There is sparse data regarding the use of cannabinoids in orthopedic surgery. Only two studies in this review had subjects solely within orthopedics [9,18]. The applicability of existing RCTs is limited by several factors, chiefly the heterogeneity of intervention and conflicting results. The evidence from non-RCTs demonstrates that cannabinoids may be an effective adjunctive analgesic and possibly curtail opioid usage. However, this is far from convincing, given the overall lack of rigor in their non-randomized design. With exceptions, cannabinoids were well-tolerated within the confines of this review, mainly causing minor AEs. The potential to serve as well tolerated analgesic adjuncts that could mitigate opioid usage make cannabinoids promising agents to investigate. The production of high-quality evidence via well designed RCTs is needed to accurately assess these effects. Attention to route of administration, dosage, choice of cannabinoid, and potential differences in gender response may be important considerations in designing future trials.

Expectations
It is of the opinion of the authors that cannabinoids may represent an adjunctive solution in providing additional analgesia in an effort to combat the overuse of opioids within orthopedic surgery. Though the current paucity of rigorous evidence makes it difficult to recommend the use of cannabinoids outside of patients involved in research trials. We would expect as legal barriers to studying these compounds continue to dissolve, more research will be performed that will better establish the usefulness of medicinal cannabinoids while better characterizing and refining indications for cannabinoid therapy within orthopedics, dosing, and route of administration. Though impossible to clearly prognosticate, the acceptance of cannabinoids as a legitimate means of pain control could alter prescribing patterns of future orthopedic surgeons and mitigate the current opioid crisis.