Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry

Figures & data

Figure 1 Patient disposition.

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; TEAE, treatment-emergent adverse event; Efficacy↓, inadequate analgesic efficacy.

Table 1 Patient demographics

Number of patients [n (%)]	800	(100.0)
Gender female [n (%)]	456	(57.0)
Ethnic origin: white/caucasian [n (%)]	750	(93.8)
Coloured african/american [n (%)]	33	(4.1)
Asian [n (%)]	17	(2.1)
Age [mean ± SD (median; range)]	46.3±9.7	(47.0; 19–77)
BMI [mean ± SD (median; range)]	27.2±5.3	(26.0; 17–73)
Pain duration [days; mean ± SD (median; range)]	1002±692.3	(911; 150–2580)
Patients with pain duration ≥1 year [n (%)]	543	(67.9)
Number of physicians involved [mean ± SD (median; range)]	8.7±1.4	(9; 3–13)
Previous pharmacological pain treatments [mean ± SD (median; range)]	9.7±2.3	(10; 4–17)
Patients with ≥10 pharmacological pretreatments [n (%)]	408	(51.0)
Pharmacological treatment with …nonopioidanalgesics [n (%)]	798	(99.8)
…mild opioids [n (%)]	567	(70.9)
…strong potent opioids [n (%)]	695	(86.9)
…antidepressants [n (%)]	704	(88.0)
…anticonvulsants [n (%)]	525	(65.6)
…muscle relaxants [n (%)]	580	(72.5)
…others [n (%)]	622	(77.8)
Previous non-pharmacological pain treatments [mean±SD (median; range)]	6.0±1.3	(6; 2–9)
Patients with ≥5 non-pharmacological pretreatments [n (%)]	701	(87.6)
Non-pharmacological treatment with …physiotherapy [n (%)]	621	(77.6)
…physical measures [n (%)]	526	(65.8)
…TENS [n (%)]	635	(79.4)
…acupuncture [n (%)]	634	(79.3)
…psychotherapy [n (%)]	604	(75.5)
…others [n (%)]	645	(80.6)
Concomittant diseases [mean ± SD (median; range)]	3.6±1.9	(3; 1–12)
Patients with ≥3 concomitant diseases [n (%)]	537	(67.1)
…allergies [n (%)]	383	(47.9)
…cardiovascular system [n (%)]	352	(44.0)
Musculoskeletal system [n (%)]	298	(37.3)
…mental/psychiatric problems [n (%)]	281	(35.1)
…pulmonary system [n (%)]	217	(27.1)
…cancer [n (%)]	110	(13.8)
…others [n (%)]	703	(87.9)
Pharmacological non-pain treatments [mean ± SD (median; range)]	2.0±1.3	(2; 0–7)
Patients with ≥2 pharmacological non-pain treatments [n (%)]	498	(62.3)
Primary condition undelying CP: (low) back pain [n (%)]	234	(29.3)
Failed back surgery syndrome [n (%)]	148	(18.5)
Shoulder/neck pain [n (%)]	91	(11.4)
Post-herpetic neuralgia [n (%)]	72	(9.0)
Peripheral (diabetic) neuropathy [n (%)]	56	(7.0)
Brachial plexus injury [n (%)]	48	(6.0)
Lumbar spinal stenosis [n (%)]	38	(4.8)
Cancer [n (%)]	31	(3.9)
Fibromyalgia [n (%)]	26	(3.3)
Peripheral/focal nerve lesions [n (%)]	22	(2.8)
Phantom pain [n (%)]	19	(2.4)
Osteoarthritis [n (%)]	15	(1.9)

Abbreviations: SD, standard deviation; BMI, body mass index; TENS, transcutaneous electrical nerve stimulation; CP, chronic pain.

Table 2 Patient baseline characteristics

Number of patients [n (%)]	800	(100)
ASA physical status 1 [n (%)]	120	(15.0)
2 [n (%)]	348	(43.5)
3 [n (%)]	332	(41.5)
4 [n (%)]	0	(0)
Stage of pain chronification … MPSS I [n (%)]	46	(5.8)
…MPSS II [n (%)]	286	(35.8)
…MPSS III [n (%)]	468	(58.5)
Chronic pain severity …stage 1 [n (%)]	0	(0.0)
…stage 2 [n (%)]	55	(6.9)
…stage 3 [n (%)]	284	(35.5)
…stage 4 [n (%)]	461	(57.6)
Tailored treatment target [TTT, mm VAS; mean ± SD (median; range)]	26.6±9.7	(25; 10–64)
Lowest 24-hour pain intensity [LPI, mm VAS; mean ± SD (median; range)]	18.6±18.8	(12; 0–88)
Average 24-hour pain intensity [API, mm VAS; mean ± SD (median; range)]	48.6±20.4	(48: 0–100)
Highest 24-hour pain intensity [HPI, mm VAS; mean ± SD (median; range)]	73.3±22.1	(80; 4–100)
24-hr. Pain intensity index [PIX, mm VAS; mean ± SD (median; range)]	46.8±16.2	(48; 2.7–89.3)
Patients with PIX ≥30 mm VAS [n (%)]	673	(84.1)
Patients with PIX ≥50 mm VAS [n (%)]	353	(44.1)
Patients with PIX ≥70 mm VAS [n (%)]	60	(7.5)
Patients with PIX ≥TTT [n (%)]	693	(86.6)
PDQ7 [NRS35; mean ± SD (median; range)]	19.0±5.4	(19; 0–35)
Clinical pain phenomenology …nociceptive [n (%)]	54	(6.8)
…mixed [n (%)]	249	(31.1)
…neuropathic [n (%)]	497	(62.1)
Pain-related disabilities in daily life [mPDI1–7, mm VAS; mean ± SD (median; range)]	66.2±17.4	(68; 7–96)
Patients with mPDI1–7≥50 mm VAS [n (%)]	626	(78.3)
Pain-related sleep problems [mPDI6, mm VAS; mean ± SD (median; range)]	66.3±23.0	(69; 0–100)
Patients with relevant sleep problems [ie mPDI6≥50 mm VAS; n (%)]	561	(70.1)
Overall well-being [MQHHF, NRS5; mean ± SD (median; range)]	1.5±1.0	(1.0; 0.0–4.9)
Patients with MQHHF ≤2.0 [n (%)]	626	(78.3)
Physical quality-of-life [SF12-PCS; mean ± SD (median; range)]	34.7±7.0	(34.0; 18.9–63.6)
Patients with SF12-PCS ≤40 [n (%)]	629	(78.6)
Mental quality-of-life [SF12-MCS; mean ± SD (median; range)]	42.6±12.0	(39.0; 21.8–72.0)
Patients with SF12-MCS ≤40 [n (%)]	432	(54.0)
Depression [DASS-D, NRS21; mean ± SD (median; range)]	16.5±4.1	(18; 4–21)
Patients with extreme depression [DASS-D ≥14; n (%)]	664	(83.0)
Anxiety [DASS-A, NRS21; mean ± SD (median; range)]	14.4±4.5	(15; 0–21)
Patients with extreme anxiety [DASS-A ≥10; n (%)]	693	(86.6)
Stress [DASS-S, NRS21; mean ± SD (median; range)]	17.9±2.1	(18; 15–21)
Patients with extreme stress [DASS-S ≥17; n (%)]	547	(68.4)

Abbreviations: ASA, American Society of Anesthesiologists Physical Status Classification System; MPSS, Mainz Pain Staging System; PDQ, pain detect questionnaire; mPDI, modified pain disability index; MQHFF, Marburg Questionnaire on Habitual Health Findings; SF₁₂, Short From 12 Health Survey; PCS, physical component score; MCS, mental component score; DASS, Depression, Anxiety, Stress Scale; NRS, Numerical Rating Scale.

Figure 2 Exposure to THC:CBD medication. Notes: mean±SD (solid line), median (dashed line in the middle), minimum and maximum (dashed lines at the bottom and top of the grey area) number of sprays per day.

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; BL, baseline; W1–12, observation weeks 1–12.

Figure 3 Change of the lowest, average and highest 24-hour pain intensities (mean ±95% CIs) during the 12-week treatment observation with THC:CBD (upper panel). Absolute and relative relief of the 24-hour pain intensity index (PIX) over the 12-week observation time (middle). Percentage of patients with ≥30%, ≥50%, and ≥70% percent improvement of the pain intensity index (PIX) over time (lower panel).

Abbreviations: BL, baseline; W1-W12, weeks 1–12; THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; PIX, pain intensity index.

Figure 4 Course of the pain intensity index (PIX) over time for patients with nociceptive, mixed, and neuropathic types of chronic pain (upper panel: absolute change, lower panel: relative change vs baseline).

Abbreviations: BL, baseline; W1-W12, weeks 1–12; THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol.

Figure 5 Proportion of patients (percent) with nociceptive (light grey), mixed (grey) and neuropathic pain (black) who reported an individual ≥50 improvement (vs baseline) with respect to pain intensity (PIX), pain-related disabilities in daily life (mPDI), sleep, overall well-being (MQHHF), physical (SF₁₂-PCS) and mental quality-of-life (SF₁₂-MCS), depression (DASS-D), anxiety (DASS-A), and stress (DASS-S) – the nine factors of the aggregated symptom relief score (ASR-9; upper panel). Proportion of patients (percent) who reported a ≥50% improvement vs baseline in 1–9 ASR-9 factors (lower panel).

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; PIX, 24-hour pain intensity index; mPDI, modified pain disability index; MQHHF, Marburg Questionnaire of Habitual Health Findings; SF12PCS, Short Form 12 Physical Component Scale; SF12MCS, Short Form 12 Mental Component Scale; DASS, Depression, Anxiety, Stress Scale; D, depression; A, anxiety; S: stress; ASR, aggregated nine-factor symptom relief score.

Figure 6 Scatterplot of the number of THC:CBD sprays per day (X-axis) vs the aggregated nine-factor symptom relief score (ASR-9; Y-axis).

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol.

Figure 7 Average change due to THC:CBD at the end of observation week 12 vs baseline with respect to the aggregated nine-factor symptom relief score (ASR-9) for CP patients with nociceptive (light grey), mixed (grey) and neuropathic pain (black).

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; PIX, 24-hr pain intensity index; mPDI, modified pain disability index; MQHHF, Marburg Questionnaire of Habitual Health Findings; SF12PCS, Short Form 12 Physical Component Scale; SF12MCS, Short Form 12 Mental Component Scale; DASS, Depression, Anxiety, Stress Scale; D, depression; A: anxiety; S, stress.

Figure 8 Correlation of the aggregated nine-factor symptom relief score (ASR-9; Y-axis) with the PDQ₇ score (X-axis) – a correlate for the involvement of neuropathic pain mechanisms (left panel). Box-(median, 25/75 percentiles; triangles: mean) and-whisker (2.5/97.5 percentile) plots of the ASR-9 symptom relief score for CP patients with nociceptive, mixed and neuropathic phenomenology.

Abbreviations: ASR-9, aggregated nine-factor symptom relief score; THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; R², correlation coefficient; PDQ-7, Seven-Dimensional Pain Detect Questionnaire.

Figure 9 Proportion of patients (percent) on THC:CBD treatment.

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; BL, baseline; W1-W12, weeks 1–12.

Figure 10 Proportion of patients (percent) with distinct capabilities to relief pain with THC:CBD (upper panel). Overall efficacy rating of THC:CBD (lower panel).

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol.

Table 3 Summary of analgesic medications taken at baseline (ie, before) and at the end of the 12-week observation period with THC:CBD

	Nociceptive pain (n=54)			Mixed pain (n=249)			Neuropathic pain (n=497)			All patients (n=800)
Maintenance analgesic treatment with	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Significance
…non-opioid analgesics [n (%)]	32(59.3)	32(59.3)	0(0.0)	101(40.6)	95(38.2)	-6(-5.9)	105(21.1)	73(14.7)	-32(-30.5)	238(29.8)	200(25.0)	-38(-16)	p=0.033
… nsaids [n (%)]	34(63.0)	34(63.0)	0(0.0)	157(63.1)	144(57.8)	-13(-8.3)	110(22.1)	97(19.5)	-13(-11.8)	301(37.6)	275(34.4)	-26(-8.6)	p=0.176
…mild opioids [n (%)]	16(29.6)	17(31.5)	1(2.6)	71(28.5)	63(25.3)	-8(-11.3)	42(8.5)	35(7.0)	-7(-16.7)	129(16.1)	115(14.4)	-14(-10.9)	p=0.330
…strong opioid analgesics [n (%)]	27(50.0)	32(59.3)	5(18.5)	178(71.5)	159(63.9)	-19(-10.7)	487(98.0)	381(76.7)	-106(-21.8)	692(86.5)	572(71.5)	-120(-17.3)	p<0.001
…antidepressants [n (%)]	21(38.9)	24(44.4)	3(9.1)	91(36.5)	88(35.3)	-3(-3.3)	291(58.6)	252(50.7)	-39(-13.4)	403(50.4)	364(45.5)	-39(-9.7)	p=0.051
…anticonvulsants [n (%)]	5(9.3)	5(9.3)	0(0.0)	100(40.2)	97(39.0)	-3(-3.0)	312(62.8)	285(57.3)	-27(-8.7)	417(52.1)	387(48.4)	-30(-7.2)	p=0.008
…others [n (%)]	9(16.7)	9(16.7)	0(0.0)	51(20.5)	50(20.1)	-1(-2.0)	308(62.0)	261(52.5)	-47(-15.3)	368(46.0)	320(40.0)	-48(-13)	p=0.015
…none [n (%)]	0(0.0)	0(0.0)	0(0.0)	0(0.0)	7(2.8)	7(2.8)	0(0.0)	7(1.4)	7(1.4)	0(0.0)	14(1.8)	14(1.8)	p<0.001
Number of maintenance analgesics [mean±SD (median)]	2.7 ± 0.9 (3)	2.8 ± 1.2 (3)		3 ± 1.1 (3)	2.8 ± 1.2 (3)		3.3 ± 0.9 (3)	2.8 ± 1.1 (3)		3.2 ± 1.0 (3)	2.8 ± 1.2 (3)	-0.4 ± 0.6 (0)
Difference W12→BL [mean±SD (median)]	0.2 ± 0.6 (0)			-0.2 ± 0.5 (0)			-0.5 ± 0.6 (0)			-0.4 ± 0.6 (0)
Demand of maintenance analgesics: 0 [n (%)]	0(0.0)	0(0.0)		0(0.0)	7(2.8)		0(0.0)	7(1.4)		0(0.0)	14(1.8)
1 [n (%)]	6(11.1)	5(9.3)		22(8.8)	33(13.3)		13(2.6)	50(10.1)		41(5.1)	88(11.0)
2 [n (%)]	14(25.9)	15(27.8)		50(20.1)	48(19.3)		29(5.8)	141(28.4)		93(11.6)	204(25.5)
3 [n (%)]	26(48.1)	19(35.2)		112(45.0)	100(40.2)		309(62.2)	195(39.2)		447(55.9)	314(39.3)
4 [n (%)]	8(14.8)	14(25.9)		41(16.5)	42(16.9)		89(17.9)	62(12.5)		138(17.3)	118(14.8)
5 [n (%)]	0(0.0)	1(1.9)		17(6.8)	15(6.0)		41(8.2)	33(6.6)		58(7.3)	49(6.1)
6 [n (%)]	0(0.0)	0(0.0)		7(2.8)	4(1.6)		16(3.2)	9(1.8)		23(2.9)	13(1.6)
Patients with …increase [n (%)]	14(25.9)			5(2.0)			0(0.0)			19(2.4)
…no change [n (%)]	35(64.8)			196(78.7)			265(53.3)			496(62)
…decrease [n (%)]	5(9.3)			48(19.3)			232(46.7)			285(35.6)
Significance	p=0.353			p=0.043			p<0.001			p<0.001
Analgesic rescue medication with	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Baseline	Week 12	Δ (W12→BL)	Significance
…non-opioid analgesics [n (%)]	10(18.5)	10(18.5)	0(0.0)	54(21.7)	43(17.3)	-11(-20.4)	123(24.7)	57(11.5)	-66(-53.7)	187(23.4)	110(13.8)	-77(-41.2)	p<0.001
… nsaids [n (%)]	24(44.4)	24(44.4)	0(0.0)	134(53.8)	112(45)	-22(-16.4)	309(62.2)	138(27.8)	-171(-55.3)	467(58.4)	274(34.3)	-193(-41.3)	p<0.001
…mild opioids [n (%)]	13(24.1)	15(27.8)	2(4.9)	74(29.7)	46(18.5)	-28(-37.8)	174(35)	101(20.3)	-73(-42)	261(32.6)	162(20.3)	-99(-37.9)	p<0.001
…strong opioid analgesics [n (%)]	5(9.3)	14(25.9)	9(18.4)	36(14.5)	31(12.4)	-5(-13.9)	111(22.3)	64(12.9)	-47(-42.3)	152(19)	109(13.6)	-43(-28.3)	p=0.004
…others [n (%)]	3(5.6)	7(13)	4(7.8)	18(7.2)	17(6.8)	-1(-5.6)	44(8.9)	39(7.8)	-5(-11.4)	65(8.1)	63(7.9)	-2(-3.1)	p=0.854
…none [n (%)]	14(25.9)	13(24.1)	-1(-7.1)	58(23.3)	102(41.0)	44(23)	77(15.5)	212(42.7)	135(32.1)	149(18.6)	327(40.9)	178(27.3)	p<0.001
Number of rescue analgesic [mean±SD (median)]	1.0 ± 0.8 (1)	1.3 ± 1.0 (1)		1.3 ± 0.9 (1)	1.0 ± 1.0 (1)		1.5 ± 0.9 (2)	0.8 ± 0.8 (1)		1.4 ± 0.9 (2)	0.9 ± 0.9 (1)	-0.5 ± 0.7 (0)
Difference W12→BL [mean±SD (median)]	0.3 ± 0.6 (0)			-0.3 ± 0.5 (0)			-0.7 ± 0.7 (-1)			-0.5 ± 0.7 (0)
Demand of rescue analgesics: 0 [n (%)]	14(25.9)	13(24.1)		58(23.3)	102(41.0)		77(15.5)	212(42.7)		149(18.6)	327(40.9)
1 [n (%)]	26(48.1)	19(35.2)		86(34.5)	70(28.1)		126(25.4)	181(36.4)		238(29.8)	270(33.8)
2 [n (%)]	13(24.1)	15(27.8)		85(34.1)	52(20.9)		247(49.7)	94(18.9)		345(43.1)	161(20.1)
3 [n (%)]	1(1.9)	7(13.0)		20(8.0)	25(10.0)		47(9.5)	10(2.0)		68(8.5)	42(5.3)
Patients with …increase [n (%)]	18(33.3)			9(3.6)			0(0.0)			27(3.4)
…no change [n (%)]	33(61.1)			164(65.9)			193(38.8)			390(48.8)
…decrease [n (%)]	3(5.6)			76(30.5)			304(61.2)			383(47.9)
Significance	p=0.104			p=0.002			p<0.001			p<0.001

Abbreviations: Δ, difference (delta); W12, week 12; BL, baseline.

Figure 11 Patient global impression of change (PGIC) ratings for THC:CBD at end of the 12-week observation period.

Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol.

Table 4 Overall treatment-emergent adverse event (TEAE) experience

	(n)	(%)
Total population	800	(100)
Subjects with at least one TEAE	159	(19.9)
Subjects with ...1 TEAE	119	(14.9)
...2 TEAEs	33	(4.1)
..3 TEAEs	7	(0.9)
Nervous system disorders	52	(6.5)
Dysgeusia	23	(2.9)
Dizziness	10	(1.3)
Drowsiness	6	(0.8)
Somnolence	5	(0.6)
Headache	3	(0.4)
Memory impairment	3	(0.4)
Disturbance in attention	2	(0.3)
Gastrointestinal disorders	42	(5.3)
Nausea	10	(1.3)
Dry mouth	14	(1.8)
Mouth discomfort	9	(1.1)
Vomiting	6	(0.8)
Diarrhea	2	(0.3)
Oral pain	1	(0.1)
General disorders and administration site conditions	23	(2.9)
Feeling abnormal	9	(1.1)
Fatigue	8	(1.0)
Application site pain	6	(0.8)
Psychiatric disorders	16	(2.0)
Disorientation	6	(0.8)
Depressed mood	5	(0.6)
Confusion	4	(0.5)
Anxiety	1	(0.1)
Metabolism and nutrition disorders	56	(7.0)
Increased appetite	50	(6.3)
Anorexia	6	(0.8)
Respiratory, thoracic and mediastinal disorders	17	(2.1)
Pharyngolaryngeal pain	14	(1.8)
Dyspnoea	3	(0.4)
Total number of TEAEs	206	(100)
Metabolism and nutrition disorders	56	(27.2)
Nervous system disorders	52	(25.2)
Gastrointestinal disorders	42	(20.4)
General disorders and administration site conditions	23	(11.2)
Respiratory, thoracic and mediastinal disorders	17	(8.3)
Psychiatric disorders	16	(7.8)
TEAE intensity …mild	168	(81.6)
…moderate	34	(16.5)
…severe	4	(1.9)
TEAE-related treatment discontinuations (pats.)	32	(4.0)
Discontinuation due to …dysgeusia	14	(1.8)
…dizziness	6	(0.8)
…fatigue	6	(0.8)
…mouth discomfort	4	(0.5)
…somnolence	2	(0.3)
Efficacy-related treatment discontinuations (pats.)	113	(14.1)
Treatment discontinuations for any reasons (pats.)	145	(18.1)