Comparing Sublingual and Inhaled Cannabis Therapies for Low Back Pain: An Observational Open-Label Study

Abstract

INTRODUCTION

Medical cannabis is rapidly becoming an acceptable treatment modality,¹ including in Israel. This was demonstrated by recent reports from the Medical Cannabis Research Unit of the Israeli Ministry of Health (IMOH). They presented data showing that the number of medical cannabis licenses issued to patients between January and February 2022 had increased by 951, of which 705 (74%) were prescribed to treat chronic neuropathic non-cancer pain (CNNCP).^2,3 Currently, active medical cannabis licenses have been issued to about 1.2% (110,971 patients) of the Israeli population, and 56.6% of such licenses were prescribed to treat CNNCP.² Nonetheless, a major obstacle to the widespread legal use of medical cannabinoid-based (CB) therapy is the lack of sufficient evidence-based data.

METHODS

Cannabis Therapy Schedule

After study enrollment, all patients underwent an initial one-month washout period (WO1) to ensure they were in a cannabis-free symptom steady state. During WO1, analgesic medication regimens were continued as before, but all cannabis use was prohibited. After WO1, phase 1 (P1) of the study was initiated and sublingual cannabis extract was administered for 10 months using a personally adjusted slow titration protocol for each participant, based on clinical evaluations. At the end of 10 months, all participants underwent a second one-month washout period (WO2), after which phase 2 (P2) was initiated and patients were switched to smoked cannabis. This latter treatment continued indefinitely, with subsequent evaluations performed every six months (Figure 1).

Figure 1

Study Timeline.

A washout period of 1 month (WO1) was followed by 10 months of cannabis extract therapy, a second 1-month washout period (WO2), and a minimum of 12 months’ inhalation therapy, which was continued indefinitely, with follow-up every 6 months.

RESULTS

Adherence to Cannabinoid-based Treatment

During phase 1 with extract treatment, 3 patients paused participation in extract therapy due to insufficient pain alleviation (Figures 1 and ​and2);2); however, they continued to be followed throughout. These 3 patients underwent observation until they stopped taking the extract; their last observation was carried forward to the end of the extract treatment phase (12 months from the enrollment to the study). Nonetheless, all 24 patients participated in WO2 and P2. Once smoked treatment P2 began, the originally planned follow-up evaluations and data collection were also resumed.

Figure 2

Summary of Participant Evaluations Throughout the Study Period (n=24*).

A: Visual analogue scale (VAS). B: Oswestry Disability Index (ODI); C: SF-12 Mental Component Score (MCS) (version 1). D: SF-12 Physical Component Score (PCS). E: Morphine Equivalent Units (MEU) opiate usage.

Results are expressed as mean±standard error (SE). Refer to Figure 1 for timing details.

* Three patients stopped treatment during phase 1 only (sometime between months 2 and 11), but remained part of the evaluations throughout the study.

The VAS pain rating score decreased for all participants overall during the study, from 83.3± 15.4 at month 0 to 39.1±18.5 at 24 months (ANOVA P<0.001). During the extract therapy phase, this decrease was not significant and averaged 12.3% (standard error [SE] 5.8, confidence interval [CI] 95% −5.3–29.8). The change in VAS was significant at 12–24 months and 12–18 months (Figure 2A; supplemental Table 1).

A similar trend was observed for the ODI, which decreased from 59.8±13.8 at month 0 (prior to WO1) to 36.9±19 at 24 months (ANOVA P<0.001). Although the ODI decrease during P1 was not significant and averaged 5.4% (SE 5.8, CI 95% −9.1 to 20.0), the decrease became significant for months 12–24 and 12–18 (Figure 2B; supplemental Table 2).

The MCS improvement was significant over the study’s duration, with an average of 36.5±11.4 at month 0 and improving to 48±9.2 at 24 months (ANOVA P<0.002). There was a significant difference between months 0, 18, and 24. Additionally, a trend for significance was found for the difference between 0–6 and 0–12 months (P>0.09) (Figure 2C). The PCS difference was significant at several time-points (Figure 2D and corresponding supplemental Tables 3 and 4). Again, no significant difference was noted from 0 to 12 months (P1).

DISCUSSION

The results of this study suggest that CB therapy is an efficacious treatment for LBP. First et al. reviewed 124 research papers and noted a sparsity of information regarding the effect of cannabis therapy on LBP symptomatology.²² Only a few studies have investigated the effects of medical CB therapy directly on chronic LBP (including our previous studies).^12,23

Our results also indicated that THC-rich smoked-cannabis inflorescence was more effective than CBD-rich cannabis-extracts for inducing symptom relief in LBP. However, due to the study design, it was impossible to rule out the possible clinical benefit of the extracts, which may have required a longer treatment duration. In addition, since the P2 smoked-cannabis therapy followed P1 extract therapy, it is possible that the longer duration of P2 treatment led to the eventual improvement in LBP symptoms.

The dried inflorescences dispensed to patients in our study had a higher THC concentration and lower CBD concentration; hence, our results suggest that THC has a positive effect in alleviating pain when consumed in accordance with the study protocol. Furthermore, the results of this study suggest that a high THC:CBD ratio is more advantageous for a therapeutic effect in LBP. Interestingly, a meta-analysis of 33 orthopedic studies suggested that results appeared to be efficacious in non-controlled studies, while appearing mixed in controlled randomized studies²⁴; furthermore, like the results of this current study, the authors found that studies using higher doses of cannabis tended to conclude that its use was effective, notwithstanding the potential for an increase in harmful effects with higher doses.²⁴

A retrospective study of cannabis extracts demonstrated anecdotal evidence of decreased pain levels and improved sleep using THC-rich cannabis extract preparations (up to 82% THC)²⁵; the authors concluded that cannabis galenical preparations may be both safe and therapeutically effective for symptomatic treatment of some chronic diseases.²⁶ Such concentrated oils are currently not allowed in Israel; however, the observed improved results may be attributed to the high THC concentration and quantity that was administered (0.5–1.0 mL per day of 82% THC oil, i.e. up to 410–820 mg THC per day). However, such a high THC dosage carries the risk of a possible increase of adverse events and their severity. Our current study had a very good safety profile with no serious adverse events, and only minor common adverse events were reported.

With regard to pain, one study has suggested further investigation of cannabigerol (CBG)-predominant CB treatments (>50% CBG), also unavailable in Israel, since 40.9% (n=127) of its patients who reported using CBG-predominant CB products to treat chronic pain had significantly less withdrawal symptoms compared to non-CBG-predominant products.²⁷

This current study included 7 (29%) females and 17 males (71%). The most commonly reported adverse events during P1 were nausea, sore throat, drowsiness, dizziness, and fatigue, all of which were transient and disappeared after dose tolerance was achieved. Most of these adverse effects were noted in female patients. Interestingly, females have been reported to have more adverse effects than males, despite presenting with pain intensities similar to those of males.²⁸ Another study reported that 1,675 (34.2%) of 4,891 respondents (no sex distribution) had at least one side effect (most commonly reported were dizziness, dry mouth, increased appetite, and sleepiness), with no serious adverse effects.¹³

Cannabidiol was also evaluated with regard to LBP. Two recent reviews noted that patients had reported a beneficial effect on chronic pain after CBD treatments; both reviews also noted that studies of CBD-rich treatments for pain were both scarce and limited, since dosing, dosing frequency, or dose combinations were not fully explored.^4,29 Nonetheless, the National Institute for Clinical Excellence has made a research recommendation for CBD in adults suffering from fibromyalgia or treatment-resistant neuropathic pain.³⁰ Interestingly, a recent survey found that 72% of 878 fibromyalgia patients who received CBD treatments instead of standard pharmaceutical therapy noted an improvement in their condition,¹¹ similarly to our previous findings in a study involving 31 fibromyalgia patients suffering from LBP, which also showed an advantage of CB therapy when compared to standard analgesic therapy.²³

The results of our study showed a significant improvement in LBP, as demonstrated by VAS, ODI, MCS, and PCS scores at 24 months. When comparing our results to those of other studies, it is important to note that some of the results were non-significant at the 12-month time-point. Nevertheless, another study with 4,166 participants receiving various cannabis treatments for different indications demonstrated that the pain intensity at six months was improved for 74.7% of their cohort and did not change for 17.8%. Moreover, of their 1,580 patients treated for CNNCP, 85.9% experienced a ≥30% improvement on the VAS pain scale, and 59.3% a >50% improvement.¹³

The high variability existing between and among cannabis strains and chemovars complicates defining the “ideal” strain in a specific clinical situation.^6,31 Aviram et al. illustrate the complex multiplicity of treatment that can be found in different studies.²⁸ From a cohort of 429, they noted that smoking was preferred by 76% of the patients, vaporizing by 20%, and 4% preferred alternating both routes of administration. Moreover, with regard to sex and CNNCP, the study noted that a total of 41 cultivars and 222 cultivar combinations were used, of which 50% were unique to males, 32% unique to females, and 18% were used by both sexes. They also noted that females had consumed different combinations than the males, with higher monthly doses of CBD and cannabichromene (CBC), and significantly lower doses of 373-15c-phytocannabinoid and the terpenoid linalool, while males had consumed higher monthly doses of cannabinol (CBN) and the terpenoid beta-myrcene and lower monthly dose of 331-18b-phytocannabinoid.²⁸

A recent six-month observational study (n= 4,364) in which patients had limited CB product options from which to choose also demonstrates the complex multiplicity of treatment options.¹³ The authors noted a significantly different treatment success rate when analyzing 1,500 patients who used only one chemovar. The varied treatment success rate was attributed to the patients’ different medical conditions.¹³ The same study also reported that 2,551 (55.7%) patients used a specific 18% THC Indica chemovar, of which 1,306 patients received inhalation therapy (average: 0.3 g [54 mg THC] inflorescence, 3.4 times a day), and 935 patients were treated with the same chemovar extract (average dose of 5.7 mg TCH per administration, 2.4 times a day).¹³

In our study, six months into P1, 21 participants had achieved the maximal dosage of 1 mL extract (30 mg CBD:5 mg THC), which had been titered up from 10 mg THC:10 mg CBD extracts; 3 participants (2 females, 1 male) had dropped out due to insufficient pain relief (Figure 2). During P1, 2 female study participants preferred the 10% THC:10% CBD inflorescences over a higher THC concentration. Interestingly, a study (n=151) evaluating the benefits of 10 mg THC:10 mg CBD cannabis extract on chronic refractory pain over 3 months reported improved pain impact scores in 47.9% of participants, unchanged scores in 28.8%, and worse scores in 23.3%; pain intensity had improved for 32.9%, remained unchanged for 45.2%, and worsened for 21.9% of the participants. The authors suggested that the reduced pain intensity influenced the patients’ quality of life, which was not reflected in the pain intensity measurements.³² Another observational study (n=3,544) reported a reduction of pain medications at 6 months, including reduction in opioid use by 52.5%, in other analgesics by 39.2%, in anti-psychotics by 36.9%, in anti-epileptics by 35.7%, and in hypnotics and sedatives by 35.3%.¹³

The monthly CB dosage distribution of all patients in the current study (Table 2) was relatively similar to the national data reported by the Israeli Medical Cannabis Unit in their January 2022 report of the general patient population in Israel (including CNNCP patients): 21–30 gram licenses were highest, representing 26.51% of total licenses issued, compared to 41.6% in our study; 31–40 gram licenses represented 23.82% compared to 29.16% in our study; 41–50 gram licenses were 17.04% compared to 12.5% in our study; and 51–60 gram licenses were issued to 8.13% compared to 8% in our study.^2,3

LIMITATIONS

In Israel there is no actual control over CB product purchases, and patients may choose from a variety of approved CB products in accordance with their cannabis prescription, which can be filled by authorized pharmacies. A standard prescription specifies the product types, grams per month, and THC:CBD ratio permitted, but not the other bioactive phytoconstituents of cannabis such as terpenes or flavonoids, which may influence treatment outcomes. Patients in Israel are not required to report which product they purchase, and CB labeling does not provide data regarding phytoconstituents other than THC, CBD, and cannabinol. Similarly, our study did not analyze CB products for chemical or toxicological phytoconstituents; hence, the chemovar characteristics that may have been beneficial to participants could not be determined. To minimize potential participant dissatisfaction with specific chemovars, the authors recommended specific ones based on their previous experience with those chemovars in LBP patients. While Israeli patients are not bound by this recommendation, they do tend to adhere to the recommended chemovar when available at pharmacies. A patient’s freedom to choose any chemovar is a disadvantage of the current study; however, this study represents real-world experience as distinguished from participants being supplied with a single chemovar. While this created some undesirable treatment variability, it increased the likelihood of participant compliance.

Another study limitation was the sample size. There are few studies that directly assess the effectiveness of CB treatments for LBP, and even fewer studies of two years’ duration and above. This study aimed to contribute to the growing knowledge in the field, and to support further studies involving larger numbers of patients for a longer duration, and with different cohorts to further elucidate knowledge regarding CB treatment modalities. With regard to sex distribution, although the male:female ratio in this study favored male patients, we do call for sex-balanced studies for the benefit of the general population.

SUMMARY

The current study is the first, to our knowledge, to indicate that THC-rich smoked therapy is more advantageous in ameliorating LBP, than low THC CBD-rich sublingual extracts. Despite the small number of patients, our data indicate that THC-rich smoked therapy is helpful in mitigating LBP. The relative strength of this study was its medium duration (up to 2 years), patient follow-ups, and multidimensional assessments that included physical and mental function, and pain and disability assessment. Further studies should be performed to assess the possible effect of THC-rich sublingual extracts compared with CBD-rich sublingual extracts for LBP treatment.

Supplementary Information

Abbreviations

Footnotes

REFERENCES