VER-01 Shows Enhanced Gastrointestinal Tolerability, Superior Pain Relief, and Improved Sleep Quality Compared to Opioids in Treating Chronic Low Back Pain: A Randomized Phase 3 Clinical Trial

Abstract

Introduction

Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments, comprising mainly non-steroidal anti-inflammatory drugs and opioids, offer limited efficacy and pose significant risks, warranting the development of tolerable, safe and effective alternatives.

Methods

This randomized controlled trial on adults with CLBP was designed to confirm the superior efficacy and gastrointestinal tolerability of VER-01, a novel, standardized full-spectrum extract from Cannabis sativa DKJ127 L., over opioids. Subjects were randomized (1:1) to receive VER-01 or a range of commercially available opioids. After a 3-week titration, subjects underwent 24 weeks of treatment, followed by 2 weeks of wash-out. The primary endpoint was the relative risk of constipation occurrence after 27 weeks treatment. Secondary endpoints included changes in pain and sleep scores, determined using an 11-point numeric rating scale (NRS), with key secondary endpoints defined for week 27.

Results

A total of 384 individuals were randomized to receive VER-01 (n = 192) or opioids (n = 192). Subjects receiving VER-01 were fourfold less likely to develop constipation than those receiving opioids (relative risk [RR] VER-01/opioids 0.25; 95% confidence interval [CI] 0.09–0.69; p = 0.007) and threefold less likely to use laxatives (RR 0.34; 95% CI 0.18–0.65; p < 0.001). Longitudinal analysis revealed that VER-01 was superior to opioids in terms of pain reduction over 6 months of treatment, although differences in secondary endpoints limited to week 27 alone were not significant. Throughout the 6 months of treatment, mean pain reduction was 2.50 NRS points with VER-01 versus 2.16 with opioids (mean difference [MD] 0.34; 95% CI 0.00–0.67; p = 0.048), and sleep improved by 2.52 points with VER-01 versus 2.07 with opioids (MD 0.45; 95% CI 0.11–0.79; p = 0.009). These benefits were particularly pronounced in participants with severe pain, with greater pain reduction (MD 0.58; 95% CI 0.01–1.15) and sleep improvement (MD 0.66, 95% CI 0.05–1.27) compared to opioids.

Conclusions

VER-01 demonstrated superiority over opioids in treating CLBP, both in terms of efficacy and gastrointestinal tolerability.

Trial Registration

ClinicalTrials.gov ID: NCT05610813; EudraCT ID: 2022-001358-41.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40122-025-00773-z.

Key Summary Points

Why carry out this study?

Chronic low back pain (CLBP) affects over half a billion people worldwide and is the leading cause of work loss, disability, and reduced quality of life

Current pharmacologic treatments, mainly comprising non-steroidal anti-inflammatory drugs and opioids, offer limited efficacy. Additionally, opioids have poor gastrointestinal tolerability and pose significant risks, including dependence and fatal overdose, warranting the development of safe, effective and non-addictive alternatives

The objective of this study was to confirm the superior safety and efficacy of VER-01, a novel, standardized full-spectrum extract from Cannabis sativa DKJ127 L., over opioids in the short- and long-term treatment of CLBP under typical clinical conditions

What was learned from this study?

Participants receiving VER-01 were significantly (fourfold) less likely to develop constipation than those receiving opioids

VER-01 was significantly more effective in alleviating pain than opioids throughout 6 months (2.50 vs. 2.16 numeric rating scale points; mean difference 0.34), with particularly pronounced effects in participants with severe pain

Introduction

Low back pain is the leading global cause of work loss, disability, and reduced quality of life across all ages and both sexes, with over half a billion prevalent cases in 2020 [1, 2]. Mechanistically, low back pain is a mixed pain condition, encompassing nociceptive, nociplastic, and neuropathic pain components [3]. Lower back pain persisting for more than 3 months is classified as chronic low back pain (CLBP). In addition to the persistent pain, sleep disturbances further impair the quality of life in these patients. The treatment of CLBP typically involves a multimodal approach that combines pharmacological and non-pharmacological interventions, such as physical activity, exercise, and physiotherapy [4, 5].

Pharmacological treatment options for CLBP include the short-term use of non-steroidal anti-inflammatory drugs (NSAIDs). However, long-term use of NSAIDs increases the risk of severe side effects, including gastrointestinal ulcers, bleeding, renal impairment, and an increased likelihood of cardiovascular events [6, 7], rendering these agents unsuitable for long-term treatment. For patients requiring long-term analgesia, opioids are frequently prescribed, despite their known severe side effects and safety concerns.

Opioid-induced constipation (OIC) is the most common severe side effect of opioids, affecting 40–60% of patients under long-term opioid therapy [8]. OIC results from the binding of opioids to receptors in the gastrointestinal tract, which reduces gut motility and secretions, leading to hardened stools and infrequent bowel movements [9–12]. This condition is often treatment-resistant, severely impairing patients' quality of life by discomfort, additional psychological distress, and interference with daily activities. [13] In many cases, the persistence of OIC can necessitate adjustments in opioid dose or discontinuation of opioid therapy, thereby placing an additional burden on patients with CLBP.

Moreover, approximately 20% of patients on long-term opioid therapy develop opioid use disorder, which is characterized by abuse, dependence, tolerance development, and withdrawal symptoms [14]. The widespread use of opioids for the management of CLBP combined with their high risk for dependence, misuse, and fatal overdoses has significantly contributed to the global opioid epidemic, resulting in hundreds of thousands of deaths worldwide [15, 16]. Accordingly, several clinical practice guidelines now advise against the use of opioids for CLBP [4, 5], and there is widespread consensus among healthcare professionals, patient organizations, and regulators on the urgent need to develop new non-addictive analgesics for the short- and long-term treatment of CLBP with a superior safety profile.

VER-01, a novel, standardized full-spectrum cannabis extract (Vertanical GmbH, Gräfelfing, Germany) has recently demonstrated robust and clinically relevant efficacy for the short- and long-term treatment of CLBP in a pivotal phase 3 study, with particularly pronounced effects in participants with a neuropathic pain component and those with severe pain [17]. Moreover, no adverse events (AEs) indicative of drug abuse, dependence, or withdrawal were reported throughout 12 months use of VER-01 during the trial. The results of this study underscore the value of a direct comparison between VER-01 and opioids for a more comprehensive understanding of VER-01’s relative efficacy and safety, especially given the widespread use of opioids for treating CLBP.

The aim of this pragmatic phase 3 trial was to close this gap and demonstrate the superior efficacy and safety of VER-01 over opioids in the treatment of CLBP.

Methods

Study Design

This pragmatic, multicenter, open-label, randomized, controlled trial was conducted at 41 outpatient sites and hospitals across Europe (Germany, Czech Republic, Poland, Spain). It was designed to investigate the short- and long-term safety and efficacy of VER-01 compared to opioids in a typical clinical setting. To this end, investigators could choose from a range of commercially available oral or transdermal opioids for subjects randomized to the opioid arm. Following titration, these subjects were free to alter their daily dose or even the choice of the opioid, if efficacy or tolerability necessitated such alterations. The trial included a 2-week run-in phase to assess baseline pain intensity, followed by 3 weeks of titration, 6 months of treatment, and a 2-week wash-out period. The trial was registered with ClinicalTrials.gov (ID: NCT05610813) and EudraCT (ID: 2022-001358-41).

Patients

Study participants were at least 18 years of age and had been diagnosed with CLBP (low back pain for at least 3 months), with or without a neuropathic pain component. Only subjects with no treatable specific somatic cause for their CLBP (e.g., herniated vertebral disk) based on a detailed medical history assessment and a clinical examination were admitted to the study. The presence of a neuropathic pain component at baseline was screened using the painDETECT questionnaire with a cut-off score > 18 [18]. Eligible subjects must have had an average pain score of at least 4 points on an 11-point numeric rating scale (NRS) 1 month before enrollment and during the run-in period. Subjects were eligible if drug treatment was indicated and previous optimized treatments with non-opioid analgesics failed to induce sufficient pain relief or were unsuitable due to contraindications or intolerance. Treatment was considered optimized when further dose escalation was medically inadvisable due to potential adverse effects, or if any additional therapeutic benefit of a higher dose was unlikely.

Participants were allowed to continue non-drug therapies for CLBP if these were maintained unchanged for at least 2 weeks prior to enrollment and continued throughout the run-in phase. Likewise, ongoing drug therapy was admissible if maintained at a stable dose throughout the run-in phase.

Subjects were excluded if they had other painful comorbidities potentially interfering with their low back pain rating, a severe mental illness (e.g., psychosis, schizophrenia, bipolar disorder), or a history of alcohol, drug, or medication abuse. A full list of inclusion and exclusion criteria is provided in the Electronic Supplementary Material (ESM) page 3–5.

Randomization

Eligible participants were randomly assigned in a 1:1 ratio to receive VER-01 or opioids via a computer-generated permuted block randomization with a block size of 4. To prevent the randomization outcome from influencing the investigator’s initial opioid selection, each participant’s assigned opioid was predetermined at the screening visit (V1). Factors to consider for the choice of the opioid were: galenic (retarded release preferred), route of administration (oral preferred), side-effect profile, concomitant diseases and medication of the participant, as well as the participant’s preferences and previous experience. Randomization was stratified based on the presence of a neuropathic (NE) pain component (NE stratum).

Procedures

The study included ten visits (Fig. 1): one at screening (V1), one after a 2-week run-in phase (randomization, V2), one at end of titration (V3), six visits at 4-week intervals during the treatment phase (V4 to V9), and a safety follow-up visit (V10).

Fig. 1.

Trial design. The trial included a 2-week run-in phase to assess baseline pain intensity, followed by 3 weeks of titration, 6 months of treatment, and a 2-week wash-out period

At screening, investigators obtained informed consent, captured patient demographics, and performed a series of examinations to assess each participant’s eligibility. These included a physical examination, self-reported psychological assessments to detect severe depression (Patient Health Questionnaire-9 [PHQ-9] [19] score > 15) or suicidal ideation (Columbia-Suicide Severity Rating Scale [C-SSRS] [20]), self-reported bowel function, a review of the participant’s medical history and prior medication(s), as well as blood samples and urine tests for drug use or pregnancy. Participants were stratified into the NE or nociceptive (NO) stratum and designated a specific opioid analgesic for subsequent administration, contingent on their randomization to the opioid arm at the next visit.

Eligible participants were instructed by site personnel on the use of the eDiary to capture patient-reported outcomes, received rescue-medication, and commenced a 2-week run-in phase. Patient-reported outcomes included pain scores, pain interference with sleep scores, AEs, and the intake of analgesics, laxatives, or rescue medication.

At V2, participants who met the randomization criteria, including an average NRS pain score ≥ 4 in the 7 days preceding V2, were randomly assigned to receive either VER-01 or their pre-specified opioid analgesic for 6 months following titration.

During all subsequent visits, investigators assessed AEs, changes in concomitant medication or non-drug therapies, laxative intake, analgesics intake, dosing of rescue medication, VER-01, and opioids. Also, participants performed a bowel function test and a urine pregnancy test (female patients) at every visit. Regular physical examinations and self-reported psychological assessments were performed throughout the treatment and wash-out phase.

Health-related quality of life was assessed at V2 (randomization), V6 (week 16), and V9 (end of treatment).

The study medication VER-01 is a standardized full-spectrum extract from Cannabis sativa strain DKJ127 L containing 21 mg (-)-trans-Δ9-tetra-hydrocannabinol (THC) per gram drug product and sesame oil as excipient. It was provided in 30-mL amber glass bottles and dispensed at the study sites during each visit throughout the treatment phase. VER-01 was taken orally with a dosing syringe, with 1 dose unit (119 µL) of VER-01 containing 2.5 mg THC, 0.1 mg cannabigerol and 0.02 mg cannabidiol. VER-01 also contains other bioactive compounds, including terpenes, with β-caryophyllene and α-bisabolol as the primary components.

Participants were advised to take VER-01 either consistently with or without food. The patient’s individual optimal dose of VER-01 was determined during a 3-week titration period following a written titration scheme. Provided that the study product was well-tolerated, the dose was increased every 3 days by 1 dose unit in the morning and by 1 dose unit in the evening until the participant either experienced sufficient symptom relief or reached the maximum daily dose of 13 dose units. The morning and evening doses were adjusted independently.

Participants randomized to opioid treatment titrated their assigned opioid according to the instructions of their investigators in compliance with the specific summary of product characteristics (SmPC). During the treatment period, the opioid dose could be adjusted upwards or downwards by the participants if their condition or concomitant medication changed, or in case of adverse reactions. Moreover, investigators were allowed to change a subject’s assigned opioid throughout the entire treatment period at their discretion, with insufficient pain relief, drug interactions or changes in liver and/or kidney function, opioid-induced hyperalgesia, or OIC as possible reasons. Opioid options included oral opioids (tilidine/naloxone, tapentadol, tramadol, oxycodone, hydromorphone, morphine) and transdermal opioids (fentanyl, buprenorphine) in commercially available doses. The proportion of patients assigned to each opioid is listed in Table 1.

Table 1.

Number of dosed subjects receiving VER-01 and comparators

Investigational product	Number of dosed subjectsa
VER-01	189
Tramadol	76
Tapentadol	49
Tilidine and naloxone	46
Oxycodone and naloxone	10
Oxycodone	7
Buprenorphine	7
Fentanyl	2
Hydromorphone	2
Morphine	2

^aMultiple assignments are possible in the opioid arm, as subjects could switch to the opioid that best suited their individual needs

Analgesic or non-drug therapies (physical or behavioral therapies) were not allowed to be started during the run-in phase; any analgesic drug therapy already applied at screening had to be continued during the run-in phase. Moreover, ongoing non-drug therapies had to be stable over a period of 2 weeks prior to screening.

The use of rescue medication (ibuprofen) was restricted to a maximum of 3 days per week and a maximum daily dose of 2400 mg. In case ibuprofen was contraindicated, paracetamol was offered at a maximum daily dose of 4000 mg.

Following treatment, participants randomized to opioids received both opioid and rescue medication at V9 to taper off opioids, whereas VER-01 was discontinued abruptly. A final visit (V10) following a 2-week wash-out phase to monitor withdrawal symptoms concluded the study.

Outcomes

The primary estimand was the relative risk (RR) for constipation occurrence at V9, as determined by the number and proportion of participants with treatment-emergent constipation. In accordance with the recommendations of the Institute for Quality and Efficiency in Health Care [21], treatment-emergent constipation was defined as a change in the overall Bowel Function Index (BFI) score of at least 15 points from baseline (V2) and an overall BFI score of > 28.8 at V9 or discontinuation of treatment due to constipation or death [22]. The BFI is a patient-reported outcome measure developed to assess constipation. It comprises three items evaluating ease of defecation, feeling of incomplete evacuation, and personal judgment of constipation, each rated on a numeric scale from 0 (no symptoms) to 100 (most severe). The mean of these items yields the total BFI score, with higher values indicating greater bowel dysfunction and a value > 28.8 indicating pathological constipation. The BFI is brief, reliable, and sensitive to clinically meaningful changes in bowel function [22].

Secondary efficacy endpoints included both eDiary-based and visit-based assessments. The first key secondary endpoint was the common risk difference (RD) in the proportion of subjects achieving a 30% reduction in the pain (NRS) score at week 27, followed by the same analysis in NE subjects only, and the RD in the proportion of subjects achieving a ≥ 30% improvement in pain-related sleep interference at week 27. Both pain and pain interference with sleep were measured twice daily on an 11-point NRS ranging from 0 (”no pain”/“not impacted”) and 10 (”worst pain imaginable”/“completely impacted”) and were captured via eDiary. Additional eDiary-based endpoints included change from baseline (CfB) (study week - 1) to end of treatment (week 27) in mean weekly pain intensity and pain interference with sleep, as well as the proportion of participants achieving ≥ 50% pain reduction, and those achieving ≥ 50% improvement in pain interference with sleep. Rescue medication use was also recorded. Pain and sleep-related outcomes were analyzed separately for participants with severe pain at baseline (NRS ≥ 7) and for the NE stratum.

Visit-based secondary efficacy endpoints included the Patient Global Impression of Change (PGIC) questionnaire [23–26], the EuroQol EQ-5D-5L questionnaire [27], the 12-Item Short Form Health Survey (SF-12) [28, 29], and the Roland Morris Disability Questionnaire (RMDQ) [30].

The PGIC is a validated, self-reported instrument using a 7-point Likert scale to assess perceived overall change in condition. Participants answered the question ‘How is your low back pain compared to before participating in the study?’ using a scale from 0 (‘very much better’) to 6 (‘very much worse’).

The EQ-5D-5L is a standardized measure for the assessment of health-related quality of life that encompasses five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain is rated on a 5-point scale, from 1 (“no problems”) to 5 (“extreme problems”). In addition, current health status is self-assessed via a visual analog scale. The resulting unique health state profile is further converted into a country-specific single index value ranging from < 0 (health state worse than death) to 1 (full health).

The SF-12 is a validated, self-reported questionnaire designed to assess health-related quality of life across physical and mental domains. It provides two summary scores, namely, the Physical Component Summary (PCS) and the Mental Component Summary (MCS), which are derived from 12 items addressing physical functioning, role limitations, pain, general health, vitality, social functioning, and mental health. The SF-12 is widely used, particularly in populations with chronic health conditions [31, 32].

The RMDQ is a validated, self-reported instrument measuring functional disability due to low back pain. It consists of 24 dichotomous (yes/no) items addressing limitations in daily activities commonly affected by back pain. The total score ranges from 0 (no disability) to 24 (maximum disability), with higher scores reflecting greater functional impairment [33, 34].

At V10, participants used the Study Medication Withdrawal Questionnaire (SMWQ) to evaluate the withdrawal symptoms following discontinuation of study medication. The SMWQ captures both physical and psychological symptoms and their impact on daily functioning. The SMWQ is applied consistently in clinical trials to evaluate tolerability during withdrawal [35].

Safety assessments included the incidence, seriousness, severity, and relationship to study drug of all AEs.

Statistical Analysis

To demonstrate the superiority of VER-01 over opioids for the primary endpoint, 320 subjects had to be randomized. This calculation was based on an assumed relative risk of 0.20 (0.03 for VER-01 and 0.15 for opioids), a one-sided significance level α = 2.50%, and 90% statistical power. We planned for 350 subjects to be randomized in a 1:1 ratio to account for premature discontinuations of study drug or withdrawal from study.

The significance level of all secondary endpoints was set to α = 5%. The sample size was calculated using SAS V9.4 (SAS Institute, Cary, NC, USA) using the one-sided Farrington-Manning score test for relative risks using the normal approximation. The 0.15 risk for constipation at V9 for subjects treated with opioids was based on a review of literature analyzing the incidence for OIC for treatment with different types of opioids [36, 37]. The risk for constipation at V9 for VER-01-treated subjects was assumed to be 0.03 based on a review of literature on patients with CLBP not undergoing drug treatment [38]. The primary estimand (relative risk of constipation occurrence) was evaluated in the full analysis set (FAS), which comprised study participants who were randomized and treated.

Statistical comparison of VER-01 and opioid treatment groups was based on the relative risk for the development of constipation, calculated as the proportion of constipation responders in the VER-01 treatment group divided by the proportion of constipation response in the opioid treatment group.

The aim of this study was to show that the risk for the development of constipation at V9 is decreased in the VER-01 treatment group by at least 20%. The corresponding one-sided statistical hypotheses were tested at the 2.5% significance level: H0: RR ≥ 0.80 vs. H1: RR < 0.80, with RR denoting the relative risk of VER-01 versus patients treated with opioids of becoming a constipation responder.

A modified Poisson regression model with robust error variances was used to compare treatment groups (VER-01 and opioids). The binary-dependent variable captured either constipation at V9 (yes/no) or the intercurrent event (ICE) (study intervention discontinuation due to constipation) or the ICE (death prior to V9), which were handled with the composite strategy. All other ICEs were handled with the treatment policy strategy. The model included the following covariates: treatment group, stratum (NO vs. NE), age group (< 65 vs. ≥ 65 years), and sex (male vs. female).

After the main estimand of the primary efficacy had been confirmed as statistically significant, the confirmatory testing approach proceeded with the testing of the first of the three key secondary efficacy variables following the hierarchical approach in the sequence using one-sided superiority hypotheses on the 2.5% one-sided alpha-level. Should the estimand of the primary endpoint or any of the following key-secondary endpoints not be confirmed to be statistically significant, the remaining key secondary endpoints were analyzed in an exploratory manner. Key secondary endpoints are listed in their hierarchical order in the Outcomes section.

All missing data were imputed with multiple imputation using the missing at random assumption (MAR) considering information from similar participants from the same treatment group, based on the above covariates, as well as baseline and observed NRS or BFI scores. Analyses were performed with SAS V9.4 (SAS Institute).

Ethical Approval

The trial was conducted at 41 outpatient sites and hospitals across Europe (Germany, Czech Republic, Poland, Spain) in compliance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonization, and applicable regulatory requirements. Approval was obtained from all relevant Ethics Committees in each participating country. A comprehensive list of independent Ethics Committees involved—classified as central or local—is provided in ESM Table S9. Written informed consent, including consent for publication of anonymized trial results, was obtained from all patients prior to enrollment.

Role of Funding

The funder (Vertanical GmbH) participated in the study design. Data collation and statistical analysis were conducted by an independent clinical research organization (CRO). The corresponding author had full access to all data and had the final responsibility for the decision to submit for publication.

Results

Between 8 June 2023 and 30 June 2024, 508 individuals were assessed for eligibility, and 384 participants were randomly assigned to receive VER-01 (n = 192) or opioid analgesics (n = 192) (Fig. 2). A total of 375 participants (61.6% female, 24.3% aged ≥ 65 years) were included in the final analysis.

Fig. 2.

CONSORT trial profile and patient flow. Of the 508 subjects assessed for eligibility, 384 were randomized to receive either VER-01 (n = 192) or opioids (n = 192). A total of 140 participants in the VER-01 group and 126 in the opioid group completed the treatment regimen. The higher discontinuation rate in the opioid arm was primarily driven by lack of efficacy, withdrawal of consent, and loss to follow-up

The two groups were balanced with respect to baseline characteristics (Table 1). Of the patients analyzed, 160 (41.7%) were suffering from severe pain (NRS ≥ 7) at baseline and 121 (32.0%) had a neuropathic pain component. The mean age of participants was 55 years, and their mean body mass index (BMI) was 29 kg/m², with no notable differences between the two groups. Baseline characteristics of participants with neuropathic pain were consistent across both treatment groups and matched those of all participants, as did those with severe pain at baseline (ESM Tables S1-S3). The most frequent concurrent diseases were arterial hypertension (33.6%) and obesity (15.2%). The proportion of subjects with at least two prior optimized analgesic therapies was balanced between treatment arms, with 94.2% in the VER-01 arm and 95.2% in the opioid arm. Among these therapies, ibuprofen was the most frequently attempted (75.7% of participants), followed by diclofenac (46.1% of participants). Pain intensity at baseline was moderate to severe in both groups, with a mean NRS pain intensity of 6.6 (standard deviation [SD] 1.3) for VER-01 and 6.6 (SD 1.4) for opioids.

The study met its primary endpoint, demonstrating a significantly higher incidence of constipation in the opioid group compared to the VER-01 group. Treatment with VER-01 was associated with a relative risk of 0.25 (95% confidence interval [CI] 0.09–0.69; p = 0.007), corresponding to fourfold less risk of constipation.

Starting immediately following titration (V3), the proportion of participants in the VER-01 arm who had developed constipation was markedly below that in the opioid arm, and this difference persisted throughout the entire 6-month treatment period (Fig. 3).

Fig. 3.

Proportion of subjects developing constipation in the VER-01 and opioids treatment arms. Subjects receiving opioids had a markedly higher incidence of constipation throughout the entire treatment period than subjects receiving VER-01

Also, laxative use was markedly reduced in the VER-01 group, with 5.8% of participants requiring laxatives versus 17.2% of those in the opioid group (p < 0.001), and a median duration of laxative use of 6.0 days compared to 21.0 days in the opioid group (ESM Table S5).

Longitudinal analysis demonstrated a significant superiority of VER-01 in terms of reducing pain over both short-term (12 weeks) and long-term (6 months) treatment, although differences in secondary endpoints assessing pain only at the last treatment week did not formally reach statistical significance (ESM Tables S6-S8).

Throughout the 12-week treatment, participants receiving VER-01 experienced a mean pain reduction of 2.33 NRS points, compared with a 1.89-point reduction in the opioid group, resulting in a mean difference (MD) of 0.44 points (95% CI 0.10–0.78; p = 0.011) in the favor of VER-01. This benefit was maintained throughout the entire 6-month treatment period, with mean reductions of 2.50 NRS points and 2.16 NRS points, respectively (MD 0.34; 95% CI  0.00–0.67; p = 0.048) in the favor of VER-01.

The superiority of VER-01 over opioids is further supported by the consistent trends in participants with a neuropathic pain component, showing a treatment difference of 0.57 NRS points in favor of VER-01 both at week 12 (95% CI -0.05–1.20) and at the end of treatment (95% CI −0.04–1.18). The superior analgesic efficacy of VER-01 was particularly notable in participants with severe pain (VER-01 n = 80; opioids n = 80), with a significant treatment difference of 0.70 NRS points in the short term (95% CI 0.12–1.28]) and 0.58 NRS points by the end of treatment (95% CI  0.01–1.15).

The superiority of VER-01 over opioids was supported by corresponding trends in longitudinal 30% and 50% pain responders, showing that participants receiving VER-01 were 16% more likely to achieve a 30% pain response (RR 1.16; 95% CI  0.99–1.37) and 19% more likely to achieve a 50% pain response (RR 1.19; 95% CI  0.92–1.54) than those receiving opioids.

The improvement in sleep interference paralleled the pain outcomes. Throughout treatment week 12, the mean CfB in NRS pain interference with sleep was 2.40 for participants receiving VER-01 compared with 1.87 for those receiving opioids, resulting in a statistically significant MD of 0.53 (95% CI  0.18–0.88; p = 0.003) in the favor of VER-01. This benefit was maintained throughout the entire 6-month treatment period, with mean reductions of 2.52 NRS points for participants receiving VER-01 compared to 2.07 for participants receiving opioids (MD 0.45; 95% CI  0.11–0.79; p = 0.009).

In participants with a neuropathic pain component (VER-01 n = 61; opioids n = 64), VER-01 demonstrated a consistent benefit in sleep, with a treatment difference of 0.82 NRS points by treatment week 12 (95% CI  0.15–1.49) and 0.84 NRS points (95% CI  0.20–1.49) by the end of treatment.

Among participants with severe pain (VER-01 n = 80; opioids n = 80), VER-01 demonstrated a higher clinical benefit on sleep with a treatment difference of 0.76 NRS points by treatment week 12 (95% CI  0.13–1.38) and 0.66 NRS points (95% CI  0.05–1.27) by the end of treatment.

Line plots of NRS pain and pain interference with sleep scores are provided in Fig. 4. These results in favor of VER-01 are further supported by the longitudinal analysis of 30% and 50% sleep responders, which showed a consistent trend favoring VER-01: participants receiving VER-01 were 13% more likely to achieve a 30% sleep response (RR 1.13; 95% CI  0.99–1.30) and 19% more likely to achieve a 50% sleep response (RR 1.19; 95% CI  0.97–1.46) compared to those receiving opioids.

Fig. 4.

Line plots of changes from baseline in numeric rating scale (NRS) pain scores (left) and NRS sleep scores (right) in both treatment arms. A Change from baseline (CfB) pain: subjects with a neuropathic pain component. B CfB sleep: subjects with a neuropathic pain component, C CfB pain, subjects with severe pain. D CfB sleep scores: subjects with severe pain. E CfB pain: full analysis set. F CfB sleep: full analysis set; wk: week

The quality of life showed consistent improvement over time in both groups. The EQ-5D-5L health index improved from an average baseline score of 0.67 (VER-01 0.69; opioids 0.66) to 0.83 (VER-01 0.84; opioids 0.81) at V6 and remained at 0.83 at V9 (VER-01 0.84; opioids 0.83).

Similarly, the SF-12 PCS improved from an average baseline score of 32.46 (VER-01 33.03, opioids 31.87) to 40.17 (VER-01 41.02; opioids 39.27) at V6 and further to 41.80 at V9 (VER-01 42.24; opioids 41.33). The SF-12 MCS remained stable in both groups, with a mean score of 52.63 (VER-01 53.01, opioids 52.24) at baseline, 52.93 at V6 (VER-01 52.97; opioids 52.88), and 52.84 at V9 (VER-01 52.99; opioids 52.67).

Subjects with treatment-emergent constipation, however, showed different trajectories. Despite a > 2 NRS point improvement in pain intensity by V9, the SF-12 PCS of participants in the opioid group with treatment-emergent constipation (n = 20) did not improve. Baseline values in this subgroup were consistent with that of the overall study population at 32.34 and did not markedly improve, with 35.05 at V6 and 33.97 at V9. Accordingly, significant differences were found in the opioid group at V9 between participants with treatment-emergent constipation (n = 20) and those without (n = 166, 42.25 at V9).

Similarly, the EQ-5D-5L health index did not meaningfully improve over time among participants with constipation within the opioid group (n = 20) (baseline 0.68; V6 0.75; V9 0.71).

A significantly higher proportion of participants in the VER-01 group experienced a clinically relevant change in the RMDQ score at V6 (69.6% vs. 56.0%; RR = 1.24; 95% CI  1.04–1.48), which is consistent with the earlier onset of pain reduction and sleep improvements observed with VER-01. In contrast, opioids achieved similar RMDQ scores only by V9 (65.8% [VER-01] vs. 65.7% [opioids]; RR 1.00; 95% CI  0.85–1.18).

Following titration, the mean daily dose of VER-01 intake remained stable throughout the entire treatment period, with 7.46 dose units at week 4 and a peak mean dosage of 7.53 dose units observed at week 5. In contrast, participants in the opioid group showed signs of dose escalation over time, as measured in morphine milligram equivalents (MME): starting from a mean value of 26.77 MME in week 4, the mean dose increased by 18% to 31.64 MME in week 25.

Treatment-emergent adverse events (TEAEs) were reported by 73.0% of participants in the VER-01 group compared to 73.7% of those in the opioid group. The most common TEAEs (≥ 10% of participants) in the VER-01 arm were dizziness (22.2%), vertigo (15.3%), nasopharyngitis (12.7%), headache (11.6%), and dry mouth (11.1%). The most common TEAEs in the opioid group were constipation (23.1%), headache (14.5%), nausea (13.4%), dizziness (11.3%), and nasopharyngitis (10.2%). Most (> 93%) of TEAEs in both groups were mild-to-moderate in nature. The rate of treatment-emergent serious adverse events (TESAEs) was comparable between the VER-01 (4.8%) and opioids (4.3%) treatment arms, and no deaths occurred during the study.

Among all participants, 12.7% of those in the VER-01 arm and 13.4% of those in the opioid arm discontinued from the intervention due to an AE. The most common AEs leading to discontinuation in the VER-01 arm were disturbance in attention (2.1%), nausea (1.6%), vomiting (1.1%), and somnolence (1.1%). The most common AEs leading to discontinuation in the opioid arm were nausea (4.3%), constipation (1.6%), and dyspnea (1.1%).

The weekly incidence of drug-related TEAEs markedly decreased in the treatment phase (VER-01 1.2%; opioids 1.1%) compared to the titration phase (VER-01 15.0%; opioids 12.5%).

Throughout the study, no clinically important treatment-related changes in clinical laboratory parameters, vital signs, or electrocardiographs were observed in participants receiving VER-01 when compared to those receiving opioids.

There were no signs of drug abuse based on urine drug tests and no withdrawal symptoms as measured with the SMWQ after treatment discontinuation.

Discussion

This phase 3, head-to-head clinical trial is the first to directly compare VER-01, a novel, standardized full-spectrum cannabis extract from Cannabis sativa DKJ127 L., with conventional opioid therapy in individuals with CLBP. Our results provide compelling evidence that VER-01 provides significantly improved gastrointestinal tolerability together with superior analgesia and sleep. VER-01 thus meets a critical unmet need in the treatment of CLBP.

Despite concerns for their long-term efficacy and safety, opioids are currently the most frequently used long-term pharmacotherapy for the management of CLBP. In particular, opioids are associated with a notable risk of addiction, tolerance development, withdrawal symptoms, opioid use disorder, neuroendocrine effects and, notably, OIC, (the latter affecting up to 60% of patients, with incidence increasing with increasing dose and type of opioid and duration of opioid use [10, 39–41]). OIC is consistently rated as the most distressing side effect of opioid use and causes significant psychological agony. The physical discomfort and accompanying psychological distress exacerbate the overall burden of opioid therapy, undermining quality of life and treatment adherence [8, 10, 39]. Consequently, in the present study, quality-of-life measures failed to improve among participants in the opioid arm who developed OIC, even though substantial pain relief was noted. In our study, VER-01 was associated with a fourfold lower risk of developing constipation, despite a significantly reduced use of laxatives, with a median duration of only 6 days compared to 21 days in opioid-treated participants.

In addition, participants treated with VER-01 achieved clinically meaningful pain reduction, outperforming potent opioids both in the short- and long-term. Notably, participants in the opioid arm were permitted to optimize their therapy by switching to the opioid that best served their individual needs at any time during the trial; however, VER-01 still demonstrated superior outcomes, highlighting the robustness of its benefit. The benefits seen with VER-01 were particularly pronounced in patients with a neuropathic pain component and those with severe pain, who are notoriously difficult to treat and have a high unmet clinical need [42, 43].

Beyond significantly alleviating chronic pain, one notable advantage of VER-01 over opioids is its ability to meaningfully improve sleep quality. Sleep disturbances are common in individuals with CLBP, contributing to inflammation, reduced pain tolerance, and increased pain severity and duration, which in turn exacerbate disability and the risk of comorbid depression [44, 45]. The respiratory depressant effects of opioids can further impair sleep quality by triggering or aggravating (obstructive) sleep apnea syndrome, a key contributor to opioid-related excess mortality [46, 47].

By demonstrating clinically meaningful superiority both in pain and sleep outcomes, VER-01 represents a promising alternative to opioids that directly targets the multifaceted burden of CLBP. These early benefits in both pain and sleep contributed to enhanced physical function, as reflected by a higher proportion of participants achieving a clinically relevant improvement in the RMDQ score by mid-study.

At the end of the study, patients in the opioid arm underwent a gradual 2-week taper to mitigate withdrawal symptoms, a well-known consequence of opioid discontinuation. In contrast, VER-01 treatment was stopped abruptly, yet no signs of withdrawal were observed. This absence of withdrawal symptoms represents a clinically meaningful advantage of VER-01 over opioid therapies and further reinforces its favorable safety and tolerability profile.

These findings are highly relevant since there is a globally recognized significant unmet medical need in the management of CLBP. Overall, these findings position VER-01 as a promising, non-addictive, well-tolerated, and effective alternative, particularly for long-term use.

It is important to note that the results of this study are specific to the unique phytochemical composition, dosing regimen, and formulation of VER-01. As a full-spectrum cannabis extract, VER-01 contains a complex mixture of cannabinoids, terpenes, and other bioactive compounds, such as cannabigerol, β-caryophyllene, and α-bisabolol, that contribute to its overall pharmacological effects. Cannabigerol has been shown to exert anti-nociceptive effects, particularly in models of neuropathic pain, while β-caryophyllene and α-bisabolol possess anti-inflammatory effects by downregulating pro-inflammatory mediators such as TNFα, IL-1β, IL-6, and NF-κB. Consequently, the results of this trial cannot be extrapolated to other cannabis-based products, including different cannabis extracts, isolated cannabinoids (such as THC or cannabidiol), or synthetic cannabinoids (such as nabilone).

The observed superiority of VER-01 in both safety and efficacy may reflect the specific profile of its constituent compounds, which distinguishes it from formulations evaluated in previous studies [48, 49]. With previous studies relying solely on placebo-controlled designs, the present study provides the first direct head-to-head comparison between a cannabis-based medicine and opioids in the treatment of chronic pain in a parallel-group design, thereby addressing a critical gap in the clinical evidence base [48].

One notable strength of our study is its reflection of everyday clinical practice with opioids, which underscores the robustness of our findings. In particular, participants randomized to opioids had the flexibility to modify their assigned dose or switch to the opioid that best suited their individual needs, mirroring real-world treatment. Yet despite the possibility to optimize opioid choice and dosage, VER-01 showed significant benefits both in efficacy and tolerability, affirming its value in enhancing patient outcomes in typical clinical settings.

A few limitations of our study merit consideration. First, the observed rate of OIC was markedly lower than the 40–60% prevalence often recorded in cross-sectional studies [8, 10, 38, 39]. We hypothesize that lower OIC rate originates in heightened physician awareness and improved patient–physician communication around OIC—an aspect known to support more effective management [11]–given the trial’s explicit focus on this outcome. Despite this limitation, the primary outcome of this trial was highly significant, underlining the markedly improved tolerability of VER-01 in comparison to opioids.

Also, while the difference in pain reduction between VER-01 and opioids did not reach statistical significance at week 27, longitudinal analysis across the entire 6-month treatment period demonstrated that VER-01 provided consistently greater symptom relief compared to opioids, reinforcing its therapeutic value beyond a single time-point assessment. Overall, the efficacy profile of VER-01 provides a compelling rationale for its use as an alternative to opioids in the management of CLBP, particularly in light of its consistent superiority across the treatment course. As in many chronic pain trials—even those of shorter duration [50–54]—this study experienced some early discontinuations, notably more so in the opioid arm. These differences were primarily driven by lack of efficacy and withdrawal of consent. However, all sensitivity analyses consistently support the primary findings (ESM Table S4), minimizing the potential impact of this limitation. Another limitation is the absence of formal cognitive assessments. While no patient-reported signs of cognitive impairment were observed, future studies involving cannabinoids might consider including specific cognitive assessments. The open-label design of this study represents a methodological limitation, as it may introduce bias related to the lack of blinding. However, this approach was necessary to allow investigators the flexibility to individualize opioid therapy—adjusting dosages or switching agents based on patient response, which closely mirrors routine clinical practice. As such, the open-label design increases the external validity of the results as it captures treatment decisions and patient outcomes in a manner reflective of real-world conditions. This pragmatic design supports the relevance and applicability of the results to everyday clinical settings, where individualized pain management is standard practice, and thus complements the preceding pivotal placebo-controlled trial of VER-01 in CLBP [17].

Conclusions

In summary, this study provides robust evidence that VER-01 offers better tolerability, as well as superior pain relief and sleep quality compared to opioids in patients with CLBP. These findings highlight its potential as a promising new pharmacological option within a multimodal treatment approach that could fundamentally shift the paradigm in the treatment of chronic pain.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Matthias Karst was clinical researcher of the trial and participated in volunteer recruitment and data acquisition. Volker Schoder participated in data management and statistical analysis. Matthias Karst, Winfried Meissner, and Volker Schoder directly accessed and verified the data. Winfried Meissner, Charles Argoff, Sabine Sator, Volker Schoder, and Matthias Karst contributed to data interpretation and to the writing, critical review and revision, and approval of the final manuscript.

Funding

This clinical trial was sponsored by Vertanical GmbH. Vertanical also funded the Rapid Service Fee for publication of this manuscript. No honoraria or payments were made for authorship.

Data Availability

Access to de-identified individual data and blank case report forms can be requested by qualified researchers for academic purposes. Vertanical GmbH provides access following review and approval of a research proposal, statistical analysis plan, and execution of a data access agreement. Data are available to request 6 months after the indication studied has been approved in the USA and the European Union and after primary publication acceptance, whichever is later, and ending 5 years after article publication. Data will be shared through a secure online platform after signing a data access agreement. Requests are to be submitted via https://vertanical.com/.

Declarations

Conflict of Interest

Winfried Meissner has received payments for advisory boards and talks from Sanofi, MSD, Tafalgie, Kyowa, Mundipharma, Grünenthal, and Ethypharm. His institution has received research support from the European Commission, Gemeinsamer Bundesausschuß (GBA), Medtronic, Pfizer, Mundipharma, Grünenthal, and Vertanical. Charles Argoff has received consultancy fees from Vertanical. Sabine Sator has received payments for speaker honoraria, advisory boards, and consensus from Grünenthal Austria, Medtronic, Ratiopharm Austria, and Novartis Austria. At the time of the study, Volker Schoder was employed by Metronomia, which was contracted to perform statistical analysis. Matthias Karst has received speaker honoraria from the Federal Association of Pharmaceutical Cannabinoid Companies (BPC), Cannabis Social Club Bolzano, Cannamedical, Demecan, Grunenthal, Hormosan, Meet Your Master, Medical Service of the Health Insurance Funds, Novartis, Stadapharm, and Tilray; consultancy fees from Tetra Pharm and Vertanical; and expert opinion fees from several local and social organizations. His institution has received research support from the Friedrich and Alida Gehrke-Foundation, German Pension Insurance Braunschweig-Hannover, Lower Saxony Ministry for Science and Culture, and Vayamed.

Ethical Approval

The trial was conducted at 41 outpatient sites and hospitals across Europe (Germany, Czech Republic, Poland, Spain) in compliance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonization, and applicable regulatory requirements. Approval was obtained from all relevant Ethics Committees in each participating country. A comprehensive list of independent Ethics Committees involved—classified as central or local—is provided in ESM Table S9. Written informed consent, including consent for publication of anonymized trial results, was obtained from all patients prior to enrollment.