Comparison of the Effectiveness and Tolerability of Nabiximols (THC:CBD) Oromucosal Spray versus Oral Dronabinol (THC) as Add-on Treatment for Severe Neuropathic Pain in Real-World Clinical Practice: Retrospective Analysis of the German Pain e-Registry

Inclusion and Exclusion Criteria

There was no formal sample size calculation for this study. Eligible GPeR datasets were those involving adult outpatients with medically confirmed peripheral neuropathic pain lasting for ≥3 months (based on explicit documentation in patients’ medical records and, as necessary, a painDETECT questionnaire [PDQ7] pain phenomenology score ≥19) and documented inadequate pain relief following recommended first- and second-line treatment for peripheral neuropathic pain. Patients were required to have newly initiated treatment with NBX or DRO between 10 March 2017 and 31 December 2019. The first dose of NBX or DRO during this period was defined as the treatment starting date. No previous use of NBX or DRO within 12 weeks of treatment initiation was permitted.

Datasets were excluded if they derived from patients with a diagnosis of cancer and/or cancer-related pain or chemotherapy-induced neuropathic pain; evidence of HIV and/or HIV-related pain; a diagnosis of osteoarthritis, complex regional pain syndrome, myofascial pain, trigeminal autonomic cephalalgia, or painful lesions of the cranial nerves not caused by post-herpetic neuralgia.

Data Analysis

Data from patients treated with NBX or DRO were propensity score matched using the nearest neighbor method (without replacement, caliper 0.15) for several baseline characteristics: age, gender, stage of chronification,³⁰ severity of chronic pain,³¹ pain phenotype, pain duration, mean 24-hr pain intensity, previous and current pain medication (Anatomical Therapeutic Chemical [ATC] code, first 3 digits and/or medication group), concomitant illnesses (ICD-10, first 3 digits), comedications (ATC code, first 3 digits), and reasons for switching medication (ineffectiveness, poor tolerability, treatment-related adverse events [TRAEs]).

Study Treatments

NBX oromucosal spray and oral DRO were used under legislative conditions for use of cannabis as pain medicine enacted by the Parliament of the Federal Republic of Germany on 10 March 2017. All analgesic treatment followed medical requirements according to the previous decision of participating physicians and was based exclusively on individual patient needs with no external specifications other than those outlined in the prescribing information of respective products.

Outcome Measures

The primary effectiveness variable was the relative (percent) change from baseline in the 9-factor Aggregated Symptom Relief (ASR-9) score over the 24-week evaluation period. The ASR-9 is a composite measure of nine distinct pain- and health-related parameters assessed using validated patient-reported instruments aimed at broadly reflecting patients’ evolution; the ASR-9 composite score is calculated as the mean of relative (percent) change rates versus baseline for the individual components. The ASR-9 is the outcome measure used to inform management decisions in the routine care of pain patients enrolled in the GPeR and was reported previously.²⁰

Secondary effectiveness outcomes were relative (percent) changes from baseline for individual components of the ASR-9: mean 24-h pain intensity index (PIX) reported on a 100 mm Visual Analogue Scale (VAS) from 0 (no pain) to 100 (worst pain conceivable); pain-related functional restrictions on activities of daily life (modified pain disability index [mPDI]) based on a 7-domain 100 mm VAS from 0 (none) to 100 (worst conceivable); physical and mental quality of life using the Veterans RAND 12-Item Health Survey (VR12-physical component score [PCS] and VR12 mental component score [MCS]);³² overall wellbeing (7-item Marburg questionnaire on habitual well-being [MFHW]);³³ pain-related depression/anxiety/stress (21-item Depression, Anxiety and Stress Scale [DASS]);³⁴ pain phenomenology assessed with the PDQ7.^35,36

Treatment response was defined by a reduction of mean 24-h PIX equal to or greater than: the minimal clinically important difference (MCID) of 20 mm VAS; 50% pain relief versus baseline reported on the VAS; the tailored treatment target as defined by patients at baseline before the onset of treatment.

Each effectiveness parameter was evaluated at baseline and at 2-weekly intervals during a 24-week evaluation period.

The safety and tolerability of NBX and DRO were assessed by analyzing the frequency and spectrum of TRAEs, and TRAEs leading to discontinuation. TRAEs were defined as events that were newly reported or reported to worsen in severity after initiation of NBX and DRO and were evaluated as being possibly, probably or definitely related to treatment. TRAEs were classified according to Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and summarized by treatment cohort.

Statistical Analyses

Analyses were conducted using propensity score matched data³⁷ from the modified intent-to-treat population which was defined as patients who had (a) documented intake of at least one dose of NBX or DRO and (b) at least one post-baseline/post-dose measure.

The primary effectiveness outcome, relative (percent) change from baseline in the ASR-9 composite score, was analyzed using a mixed-model repeated measures (MMRM) covariance analytic method. The least squares means (LSM) difference in the ASR-9 score between treatments (NBX minus DRO) during the 24-week evaluation period (at 2-weekly intervals) and 95% confidence intervals (CI) were calculated using the model. Non-inferiority of NBX to DRO was concluded if the upper boundary of the 95% CI did not exceed +5.0. This narrow margin was selected to prevent super-interpretation of minor differences. If non-inferiority was demonstrated, a superiority analysis of the primary endpoint was to follow. Superiority was rejected if a) the 95% CI for the primary endpoint measure of both treatment cohorts overlapped; and/or b) the 95% CI of the LSM difference for the primary efficacy variable between both treatment groups included “0”; and/or c) the upper limit of the 95% CI was greater than −5.0; and/or d) ≥ one ASR-9 parameter failed to meet any of the above criteria. Using a multidimensional approach, the superiority of NBX was confirmed if a) all the above efficacy criteria were fulfilled and b) the incidence of treatment discontinuations due to TRAEs was significantly less in the NBX cohort than in the DRO cohort.

Descriptive statistics for continuous variables are summarized by number of patients, mean, standard deviation (SD), standard error (SE), 95% CI, median and range. Categorical and ordinal variables are summarized by frequency and percentage. Where applicable, 95% CI, Student’s t-test and Pearson’s chi-squared tests were used to compare groups with continuous or categorical variables. Differences in discontinuation rates between NBX and DRO treatment groups were evaluated using Fisher’s exact test. The baseline observation carried forward (BOCF) method was used to impute data missing due to treatment discontinuations in response to TRAEs or analgesic ineffectiveness, and the last observation carried forward (LOCF) method was used for all other missing values, except for dosage data which was analyzed as reported. All statistical tests were conducted using 2-tailed tests and a significance level of 0.05. No adjustments were made for multiple testing.

Treatment Discontinuations

By week 24, 80 patients (23.7%) treated with NBX and 134 patients (39.8%) treated with DRO had discontinued treatment, most commonly due to ineffectiveness (9.2 vs 13.1%, p<0.001) and TRAEs (5.9 vs 14.8%, p<0.001). Nine of ten discontinuations in both cohorts (91.3 vs 91.8%) occurred within the first 10 weeks of treatment. No further discontinuations were reported beyond week 14 (Figure 2).

Study Medication Exposure

During the 24-week evaluation period, the applied mean (SD) dose of THC was slightly (but significantly) lower in patients treated with NBX than DRO [16.6 (6.5) vs 17.2 (7.6) mg/day; p<0.001] (Table 2). This was mainly attributable to clinically relevant dosage differences until week 8, with higher THC dosages recorded in DRO- versus NBX-treated patients. After week 8 and to the end of week 24, between-cohort THC dosages were comparable. The mean (SD) CBD dose in the NBX cohort during the 24-week evaluation period was 15.4 (4.1) mg/day.

Effectiveness

Relative change from baseline over time in the ASR-9 composite score and individual components are shown in Figure 3. At the end of week 24, mean relative change (improvement) versus baseline in the ASR-9 composite score (primary effectiveness outcome) was significantly greater with NBX (Figure 3A) than DRO (Figure 3B): 60.8% vs 46.4% (LSM difference 14.4%; p<0.001; Cohen’s d effect size, 1.268). Mean relative change (improvement) rates at the end of week 24 for each ASR-9 component were significantly greater (all p<0.001) for patients treated with NBX (Figure 3A) than DRO (Figure 3B): 83.4 vs 75.9% for PIX, 76.0 vs 68.3% for mPDI, 27.8 vs 20.7% for VR12-PCS, 24.7 vs 18.4% for VR12-MCS, 64.1 vs 51.3% for MFHW, 70.5 vs 51.5% for DASS-D, 78.4 vs 52.3% for DASS-A, 80.7 vs 50.3% for DASS-S, and 40.8 vs 31.8% for PDQ7. The largest between-cohort differences in favor of NBX versus DRO at the end of week 24 were observed for stress (30.5%; effect size: 3.313), anxiety (26.2%; effect size: 1.526), depression (19.0%, effect size: 0.862), and overall wellbeing (12.8%; effect size: 0.862); the smallest difference was observed for pain phenomenology (9.0%; effect size: 0.288) (Figure 3C and ​andDD).

Throughout the 24-week evaluation period, NBX and DRO were each associated with significant improvements compared with baseline for evaluated (lowest, medium, highest) 24-hour pain intensity scores and calculated 24-hour PIX (all p<0.001; Table 3). However, mean (SD) absolute [36.8 (13.1) vs 33.3 (12.4) mm VAS] and relative [83.4 (12.6) vs 75.9 (17.0) percent] PIX improvement from baseline was significantly higher with NBX than DRO (p<0.001 for both). Response rates for patients who reported an improvement from baseline in mean 24-h PIX equal to or greater than a) the MCID of 20 mm VAS (92.0 vs 86.9%; p=0.006), b) 50% improvement in VAS score (98.8 vs 95.3%; p=0.002), and c) the tailored treatment target (95.8 vs 89.6%; p<0.001) were clinically relevant for both treatments, although significantly higher with NBX versus DRO (Table 3).

Figure 4 shows response rates of patients treated with NBX (Figure 4A) or DRO (Figure 4B) who reported improvement from baseline in the ASR-9 composite score and individual components over the 24-week evaluation period, according to level of achievement (≥10%, ≥20%, etc.). An ASR-9 response of ≥50% relative to baseline was reported by 64.4 vs 22.8% of patients treated with NBX or DRO (p<0.001; odds ratio [OR]: 6.1, relative risk [RR]: 2.8; Figure 4C). Median percent ASR-9 improvement relative to baseline was 55.4 vs 40.5% (LSM difference 14.0; 95% CI: 12.6–15.4; Cohen’s d effect size: 0.9; Figure 4D). For any given response achievement level, and for all ASR-9 components, NBX was superior to DRO, with the highest between-cohort responder rate differences observed for stress (DASS-S: 45.5%), anxiety (DASS-A: 35.8%), and depression (DASS-D: 31.0%). Improvement rates of ≥50% relative to baseline were reported by 89.3 vs 78.6% of patients treated with NBX or DRO for PIX, 91.1 vs 75.1% for mPDI, 15.1 vs 7.8% for VR12-PCS, 10.9 vs 3.7% for VR12-MCS, 70.5 vs 51.3% for MFHW, 74.5 vs 43.6% for DASS-D, 79.2 vs 43.3% for DASS-A, 85.2 vs 39.8% for DASS-S, and 33.2 vs 24.0% for PDQ7. Responder rates were accompanied by comparable median percent improvements versus baseline in both treatment cohorts.

Mean effect sizes (Cohen’s d) for between-cohort differences reported from weeks 2 to 24 for relative improvement from baseline in the ASR-9 composite score and individual components are shown in Figure 5. According to Cohen’s d statistic, between-cohort differences in favor of NBX versus DRO were large (ie >0.8) for the ASR-9 composite score (0.893, 95% CI: 0.735–1.051), and for the individual components of stress (DASS-S: 1.323) and anxiety (DASS-A: 0.852). Effect sizes for depression (DASS-D: 0.598), mental component score (VR12-MCS: 0.546), and pain-related disability (mPDI: 0.538) were medium. Effect sizes for pain intensity (PIX: 0.320), physical component score (VR12-PCS: 0.400), overall wellbeing (MFHW: 0.436), and pain phenomenology (PDQ7: 0.288) were small.

Safety and Tolerability

Overall, 102 TRAEs were recorded by 71 patients (21.1%) treated with NBX, and 235 TRAEs were recorded by 118 patients (35.0%) treated with DRO (p<0.001; OR: 2.0, RR: 1.7, number need to harm [NNH]: 7.2; Table 4). A significantly lower proportion of NBX- versus DRO-treated patients reported ≥ two TRAEs (6.5 vs 21.1%, p<0.001; OR: 3.8, RR: 3.2, NNH: 6.8) or experienced TRAEs leading to treatment discontinuation (5.9 vs 14.8%; p<0.001; OR: 2.8, RR: 2.5, NNH: 11.2). By SOC, incidences of TRAEs were significantly lower with NBX than DRO for general disorders and administration site conditions (1.8% vs 5.9%; p<0.001), nervous system disorders (9.5 vs 19.9%; p<0.001) and psychiatric disorders (4.2% vs 14.8%; p<0.001).

Primary Endpoint Noninferiority Superiority Analysis

Both NBX and DRO significantly improved the ASR-9 composite score from baseline during the 24-week evaluation period (p<0.001 for both). Median (SE) ASR-9 improvement was 55.4% (0.502) and 40.5% (0.502), respectively. The LSM (SE) difference was 14.0 (0.711) with a 95% CI of 12.6 to 15.4 (p<0.001), thus fulfilling predefined criteria for noninferiority of NBX versus DRO. Given that the primary endpoint fulfilled all predefined prerequisites (ie no overlap of 95% CIs, 95% CIs of LSM did not include 0, upper 95% CI was > −5.0), a superiority analysis was performed, as defined in the statistical analysis plan. All 10 predefined superiority criteria were fulfilled, thus confirming the superiority of NBX over DRO.

Editorial assistance was provided by Robert Furlong and Kerry Dechant on behalf of Content Ed Net (Madrid, Spain) with funding from Almirall S.A. (Barcelona, Spain).