Cost-effectiveness of tapentadol prolonged release compared with oxycodone controlled release in the UK in patients with severe non-malignant chronic pain who failed 1st line treatment with morphine

Figures & data

Figure 1.  Simplified Markov model structure. AEs, adverse events; TDF, transdermal fentanyl; TDB, transdermal buprenorphine.

Table 1.  Probabilities of withdrawal due to AEs, withdrawal due to lack of efficacy, and AEs not leading to withdrawal for tapentadol and oxycodone.

	Total population						Sub-group
	Tapentadol			Oxycodone			Tapentadol			Oxycodone
	No. of patients	No. of patients at the start of the cycle	%	No. of patients	No. of patients at the start of the cycle	%	No. of patients	No. of patients at the start of the cycle	%	No. of patients	No. of patients at the start of the cycle	%
Withdrawal due to AEs
Data for whole trial duration (15 weeks)	179	980	18.27	394	1001	39.36	56	311	18.01	87	285	30.53
Cycle 1: Day 1–28 (trial data)	120	980	12.25	324	1001	32.37	35	311	11.25	70	285	24.56
Cycle 2: Day 28–56 (trial data)	45	716	6.29	50	539	9.28	19	226	8.41	11	181	6.08
Cycle 3: Day 56–84 (trial data)	11	620	1.77	17	448	3.80	2	185	1.08	5	161	3.11
Cycle 4: Day 84–112 (trial data)	3	579	0.52	3	405	0.74	0	173	0.00	1	148	0.68
Cycle 5–13: Day 112+ (extrapolated)^a			0.63			0.63			0.34			0.34
Withdrawal due to lack of efficacy
Data for whole trial duration (15 weeks)	61	980	6.22	34	1001	3.40	27	311	8.68	15	285	5.26
Cycle 1: Day 1–28 (trial data)	46	980	4.69	21	1001	2.10	18	311	5.79	11	285	3.86
Cycle 2: Day 28–56 (trial data)	15	716	2.10	6	539	1.11	9	226	3.98	1	181	0.55
Cycle 3: Day 56–84 (trial data)	0	620	0.00	5	448	1.12	0	185	0.00	1	161	0.62
Cycle 4: Day 84–112 (trial data)	0	579	0.00	2	405	0.49	0	173	0.00	2	148	1.35
Cycle 5–13: Day 112+ (extrapolated)^a			0.25			0.25			0.68			0.68
AEs no leading to withdrawal^b
Data for whole trial duration (15 weeks)	536	980	54.69	464	1001	46.35	164	311	52.73	159	285	55.79
Cycle 1: Day 1–28 (trial data)	492	980	50.20	473	1001	47.25	155	311	49.84	153	285	53.68
Cycle 2: Day 28–56 (trial data)	213	716	29.75	148	539	27.46	70	226	30.97	67	181	37.02
Cycle 3: Day 56–84 (trial data)	167	620	26.94	117	448	26.12	49	185	26.49	50	161	31.06
Cycle 4: Day 84–112 (trial data)	154	579	26.60	135	405	33.33	46	173	26.59	49	148	33.11
Cycle 5–13: Day 112+ (extrapolated)^a			29.97			29.97			29.85			29.85
No withdrawal and no AEs
Cycle 1: Day 1–28	–	–	32.86	–	–	18.28	–	–	33.12	–	–	17.90
Cycle 2: Day 28–56	–	–	61.86	–	–	62.15	–	–	56.64	–	–	56.35
Cycle 3: Day 56–84	–	–	71.29	–	–	68.96	–	–	72.43	–	–	65.21
Cycle 4: Day 84–112	–	–	72.88	–	–	65.44	–	–	73.41	–	–	64.86
Cycle 5–13: Day 112+	–	–	69.15	–	–	69.15	–	–	69.13	–	–	69.13

^aAverage probabilities of the outcomes between tapentadol and oxycodone in the 4th cycle were extrapolated to the remaining time horizon.

^bTotal number of patients with need for medical treatment was calculated as total no. of subjects with AEs minus number of patients who withdraw due to AEs.

AEs, adverse events.

Table 2.  Probabilities of withdrawal due to AEs, withdrawal due to lack of efficacy, and AEs not leading to withdrawal for TDF, TDB, and oxycodone/naloxone combination.

	TDF		TDB		Oxycodone/naloxone
	Total population (%)	Sub-group (%)	Total population (%)	Sub-group (%)	Total population (%)	Sub-group (%)
Withdrawal due to AEs
Data for whole trial duration (12 months)^a	24.81	24.81	31.43	31.43	3.90	3.90
Cycle 1: Day 1–28^b	18.52	17.73	23.46	22.47	2.91	2.79
Cycle 2: Day 28–56^b	7.19	8.26	9.11	10.47	1.13	1.30
Cycle 3: Day 56–84^b	2.40	2.01	3.04	2.54	0.04	3.10
Cycle 4: Day 84–112^b	0.59	0.03	0.74	0.35	0.09	0.04
Cycle 5–13: Day 112+^c	0.63	0.04	0.79	0.47	0.01	0.06
Withdrawal due to lack of efficacy
Trial duration (12 months)^d	7.44	7.44	26.67	26.67	2.60	2.60
Cycle 1: Day 1–28^b	5.11	5.21	18.29	18.67	1.78	1.82
Cycle 2: Day 28–56^b	2.47	2.10	8.86	7.52	0.86	0.73
Cycle 3: Day 56–84^b	1.22	0.44	4.38	1.57	0.48	0.15
Cycle 4: Day 84–112^b	0.54	0.96	1.94	3.42	0.19	0.33
Cycle 5–13: Day 112+^c	0.42	0.77	0.02	2.75	0.15	0.27
AEs no leading to withdrawal
Trial duration (12 months)^e	48.00	48.00	40.00	40.00	51.95	51.95
Cycle 1: Day 1–28^b	46.50	45.78	38.75	38.15	50.32	49.54
Cycle 2: Day 28–56^b	27.27	30.02	22.73	25.02	29.51	32.49
Cycle 3: Day 56–84^b	25.34	25.42	21.12	21.18	27.43	27.51
Cycle 4: Day 84–112^b	28.93	26.34	24.11	21.95	31.31	28.51
Cycle 5–13: Day 112+^c	28.66	26.43	23.89	22.02	31.02	28.60
No withdrawal and no AEs
Cycle 1: Day 1–28^b	31.28	31.28	19.50	20.71	44.99	45.85
Cycle 2: Day 28–56^b	59.62	59.62	59.30	56.99	68.50	65.48
Cycle 3: Day 56–84^b	72.13	72.13	71.46	74.71	72.05	69.24
Cycle 4: Day 84–112^b	72.67	72.67	73.21	74.28	68.41	71.12
Cycle 5–13: Day 112+^c	72.76	72.76	75.30	74.76	68.82	71.07

^aThe probabilities for the overall trial duration were derived from the clinical trials: TDF: n = 383 (24.81%); TDB: n = 105 (31.43%); oxycodone/naloxone: n = 6 (3.90%). Duration of TDF trial was 6 months.

^bIt was assumed that TDF, TDB, and oxycodone/naloxone combination have the same ratio between the probability of the outcome in the specific cycle vs the probability for the whole trial period as it is observed for tapentadol and oxycodone.

^cAverage probabilities of the outcomes between tapentadol and oxycodone in the 4th cycle were extrapolated to the remaining time horizon.

^dThe probabilities for the overall trial duration were derived from the clinical trials: TDF: n = 39 (7.44%); TDB: n = 28 (26.67%); oxycodone/naloxone: n = 4 (2.60%).

^eThe probabilities for the overall trial duration were derived from the clinical trials: TDF: n = 253 (48.00%); TDB: n = 42 (40.00%); oxycodone/naloxone: n = 80 (51.95%).

AEs, adverse events; TDF, transdermal fentanyl; TDB, transdermal buprenorphine.

Table 3.  Total daily opioid doses applied in the model.

	TDD (mg)
	Total population	Sub-group
Tapentadol PR
Titration	240	252
Maintenance	350	392
Oxycodone CR
Titration	40	47
Maintenance	65	75
Morphine^a
Titration	80	94
Maintenance	130	149
TDF^b
Titration	0.8	0.9
Maintenance	1.3	1.4
TDB^c
Titration	0.9	1.1
Maintenance	1.5	1.8
Oxycodone/naloxone combination^d
Titration	40	47
Maintenance	65	75

^aMorphine is not considered as an option in the UK model; however, it was required to calculate drug doses for the listed opioids. EDR morphine to oxycodone 1:2.

^bEDR morphine to TDF 100:1.

^cEDR morphine to TDB 70–100:1; for calculation the average value of 85 was applied.

^dEDR oxycodone to oxy./nalox. 1:1.

CR, controlled-release; PR, prolonged release; TDD, total daily dose; TDF, transdermal fentanyl.

Table 4.  Model relevant daily drug costs.

	Total population			Sub-group
	TDD (mg)	Costs per mg (£)	DTC (£)	TDD (mg)	Costs per mg (£)	DTC (£)
Tapentadol
Titration	240	0.0089	2.14	252	0.0089	2.24
Maintenance	350		3.11	392		3.49
Oxycodone
Titration	40	0.0445	1.78	47.1	0.0445	2.10
Maintenance	65		2.89	74.7		3.32
TDF
Titration	0.8	2.8549	2.28	0.94	2.8549	2.69
Maintenance	1.3		3.71	1.49		4.27
TDB
Titration	0.94	1.1696	1.10	1.11	1.1696	1.30
Maintenance	1.53		1.79	1.76		2.06
Oxy./nalox
Titration	40	0.0627	2.51	47	0.0627	2.95
Maintenance	65		4.08	75		4.68
4th line
Titration			1.92^a			2.26^c
Maintenance			3.12^b			3.58^d

^aAverage value of DTC for oxycodone, TDF, TDB, and oxy./nalox. (titration), i.e., (1.78 + 2.28 + 1.10 + 2.51)/4.

^bAverage value of DTC for oxycodone, TDF, TDB, and oxy./nalox. (maintenance), i.e., (2.89 + 3.71 + 1.79 + 4.08)/4.

^cAverage value of DTC for oxycodone, TDF, TDB, and oxy./nalox. (titration), i.e., (2.10 + 2.69 + 1.30 + 2.95 + 2.24)/4.

^dAverage value of DTC for oxycodone, TDF, TDB, and oxy./nalox. (maintenance), i.e., (3.32 + 4.27 + 2.06 + 4.68 + 3.49)/4.

DTC, daily total costs; oxy./nalox., oxycodone/naloxone combination; TDD, total daily dose; TDF, transdermal fentanyl.

Table 5.  Model relevant costs for physician visits and co-medication.

Opioid monotherapy	Costs (£)
2nd line
Regular treatment: ‘no withdrawal and no AEs treated’	156.86
‘Expanded’ treatment: ‘withdrawal due to adverse events’, ‘AEs not leading to withdrawal’ or ‘withdrawal due to lack of efficiency’	211.90
3rd line
Regular treatment: ‘no withdrawal and no AEs treated’	210.91
‘Expanded’ treatment: ‘withdrawal due to adverse events’, ‘AEs not leading to withdrawal’ or ‘withdrawal due to lack of efficiency’	272.08
4th line
Average costs (assumption)*	241.49

*Costs calculated as average of 2nd and 3 rd line ‘Expanded’ treatment.

AEs, adverse events.

Table 6.  Model relevant utility weights for the total population and sub-group.

Health state utility values (EQ-5D health status indices)	Tapentadol		Oxycodone		Weighted average^a
	Mean value (SD)	n	Mean value (SD)	n	Mean value (SD)
Total population
AEs not leading to withdrawal
Baseline	0.42 (0.31)	715	0.43 (0.30)	856	0.425 (0.300)
End-point	0.61 (0.26)	715	0.56 (0.28)	856	0.583 (0.272)
Withdrawal due to AEs
Baseline	0.43 (0.30)	179	0.43 (0.30)	390	0.430 (0.300)
End-point	0.51 (0.29)	179	0.50 (0.29)	390	0.503 (0.290)
Withdrawal due to lack of efficacy
Baseline	0.36 (0.30)	61	0.40 (0.32)	34	0.374 (0.310)
End-point	0.40 (0.29)	61	0.42 (0.32)	34	0.405 (0.300)
No withdrawal and no AEs
Baseline	0.45 (0.30)	146	0.42 (0.30)	69	0.443 (0.300)
End-point	0.69 (0.25)	146	0.70 (0.20)	69	0.695 (0.235)
4th line therapy^b					0.422 (0.302)
Sub-group
AEs not leading to withdrawal
Baseline	0.31 (0.30)	220	0.36 (0.31)	245	0.336 (0.306)
End-point	0.53 (0.30)	220	0.54 (0.29)	245	0.535 (0.294)
Withdrawal due to AEs
Baseline	0.31 (0.30)	56	0.34 (0.29)	85	0.328 (0.293)
End-point	0.42 (0.32)	56	0.44 (0.29)	85	0.432 (0.301)
Withdrawal due to lack of efficacy
Baseline	0.25 (0.31)	27	0.25 (0.33)	15	0.250 (0.313)
End-point	0.32 (0.32)	27	0.32 (0.36)	15	0.321 (0.329)
No withdrawal and no AEs
Baseline	0.35 (0.32)	39	0.36 (0.31)	20	0.355 (0.311)
End-point	0.60 (0.28)	39	0.66 (0.16)	20	0.622 (0.242)
4th line therapy^a					0.310 (0.299)

^aUtilities for health states were obtained by the weighted average of tapentadol and oxycodone values at end-point.

^bBaseline of patients who withdrew (assumption), calculated as a weighted average of withdrawal due to AEs and lack of efficacy).

AEs, adverse events; SD, standard deviation.

Table 7.  Summary of model relevant utility weights.

	Total population		Sub-group
	Mean annual value (SE)	Mean value per cycle	Mean annual value (SE)	Mean value per cycle
No withdrawal and no AEs	0.695 (0.016)	0.053	0.622 (0.030)	0.052
Mild-to-moderate AEs not leading to withdrawal	0.583 (0.007)	0.045	0.535 (0.014)	0.045
Withdrawal due to AEs	0.503 (0.012)	0.039	0.432 (0.025)	0.036
Withdrawal due to lack of efficacy	0.405 (0.031)	0.031	0.321 (0.051)	0.027
4th line therapy*	0.422 (0.012)	0.032	0.310 (0.022)	0.026

*Utility for patients who withdraw (assumption). Measured at baseline in the clinical trials.

AEs, adverse events; SE, standard error.

Table 8.  Model relevant treatment switches.

From/to	3rd line oxycodone/ naloxone	3rd line TDF	3rd line TDB
2nd line oxycodone/tapentadol	0.31	0.62	0.07

TDB, transdermal buprenorphine; TDF, transdermal fentanyl.

Table 9.  Outcomes (total costs and QALYs), total population, and sub-group.

Strategy	Total population		Sub-group
	Mean costs per patient (£)	Effects (QALYs)	Mean costs per patient (£)	Effects (QALYs)
2nd line tapentadol	3542.83	0.6371	3702.68	0.5658
2nd line oxycodone	3656.23	0.6237	3754.10	0.5587

QALYs, quality adjusted life years.

Figure 2.  Cost-effectiveness planes for base-case analysis, total population (a), and sub-group (b). GBP, British pound sterling; QALY, quality adjusted life year.

Table 10.  Impact on the incremental costs and effectiveness in one-way sensitivity analyses, three most influential variables (2nd line tapentadol vs 2nd line oxycodone).

	Incremental costs (£)	Incremental QALYs	ICER
Total population
Utility of patients who did not withdraw and had no AEs (−20%)	−113.40	0.0068	Tapentadol dominates
Utility of patients who did not withdraw and had no AEs (+20%)	−113.40	0.0201	Tapentadol dominates
Regular treatment costs (−50%)	−47.23	0.0134	Tapentadol dominates
Regular treatment costs (+50%)	−179.57	0.0134	Tapentadol dominates
Utility in 4th line treatment (−20%)	−113.40	0.0169	Tapentadol dominates
Utility in 4th line treatment (+20%)	−113.40	0.0104	Tapentadol dominates
Sub-group
Utility of patients who did not withdraw and had no AEs (−20%)	−51.42	0.0031	Tapentadol dominates
Utility of patients who did not withdraw and had no AEs (+20%)	−51.43	0.0110	Tapentadol dominates
Regular treatment costs (−50%)	−21.43	0.0072	Tapentadol dominates
Regular treatment costs (+50%)	−81.41	0.0072	Tapentadol dominates
Probability of ‘withdrawal due to AEs’ for oxycodone (−20%)	−9.09	0.0037	Tapentadol dominates
Probability of ‘withdrawal due to AEs’ for oxycodone (+20%)	−89.12	0.0103	Tapentadol dominates

QALYs, quality adjusted life years; AEs, adverse events.

Figure 3.  ICE scatter plots of 2nd line tapentadol vs 2nd line oxycodone; total population (a) and sub-group (b); 5000 simulation runs. QALY, quality-adjusted life year; WTP, willingness to pay.

Figure 4.  CEACs for 2nd line tapentadol vs 2nd line oxycodone. QALY, quality-adjusted life year; WTP, willingness to pay.