Tapentadol Prolonged Release for Long-Term Treatment of Pain in Children

Figures & data

Table 1 Baseline Characteristics

	Randomized Treatment		Extension Phase
	Tapentadol PR (n=45)	Morphine PR (n=24)	Tapentadol PR (n=36)
Sex
Female	22 (48.9%)	10 (41.7%)	23 (63.9%)
Male	23 (51.1%)	14 (58.3%)	13 (36.1%)
Age groups
6 to <12 years	12 (26.7%)	7 (29.2%)	10 (27.8%)
12 to <18 years	33 (73.3%)	17 (70.8%)	26 (72.2%)
Race
White	44 (97.8%)	24 (100%)	36 (100%)
Native Hawaiian or other Pacific Islander	1 (2.2%)	0	0
Ethnicity
Hispanic or Latino	7 (15.6%)	4 (16.7%)	10 (27.8%)
Not Hispanic or Latino	36 (80%)	20 (83.3%)	24 (66.7%)
Missing	2 (4.4%)	0	2 (5.6%)
Bodyweight (kg)	49.0 (19.3–85.1)	54.3 (20–70)	53.8 (19.3–83)
Body mass index (kg/m^2)	18.9 (13–33.7)	19.8 (12.4–27)	20.8 (13–33.7)
Cause of pain
Cancer-related	9 (20%)	5 (20.8%)	8 (22.2%)
Not cancer-related	36 (80%)	19 (79.2%)	28 (77.8%)
Type of pain
Neuropathic	9 (20%)	4 (16.7%)	11 (30.6%)
Nociceptive	29 (64.4%)	14 (58.3%)	18 (50%)
Mixed pain	7 (15.6%)	6 (25%)	7 (19.4%)
Pain intensity^a
VAS	47.8±32.4^b	50.8±32.5^b	30.8±32.3^c
FPS-R	4.6±3.3^b	4.2±3.0^b	3.3±3.2^c

Notes: Data are number of patients (%), median (range) or mean ± standard deviation. ^aMissing data for randomized treatment phase: tapentadol PR n=13, morphine PR n=5; for extension phase: n=4; ^bBaseline of randomized treatment; ^cBaseline at start of extension.

Abbreviations: FPS-R, Faces Pain Scale-Revised; VAS, visual analogue scale.

Table 2 Underlying Diagnosis/Reason for Pain

	Randomized Treatment		Extension Phase
	Tapentadol PR (n=45)	Morphine PR (n=24)	Tapentadol PR (n=36)
Congenital, familial and genetic disorders  Congenital neuropathy  Developmental hip dysplasia  Ehlers-Danlos syndrome  Klippel-Trenaunay syndrome  Neurofibromatosis  Pectus excavatum  Sickle cell anemia  Talipes	8 (17.8%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 0 2 (4.4%) 1 (2.2%) 1 (2.2%)	4 (16.7%) 0 0 0 0 1 (4.2%) 3 (12.5%) 0 0	7 (19.4%) 1 (2.8%) 1 (2.8%) 1 (2.8%) 1 (2.8%) 1 (2.8%) 0 1 (2.8%) 1 (2.8%)
Gastrointestinal disorders  Constipation	1 (2.2%) 1 (2.2%)	0 0	1 (2.8%) 1 (2.8%)
Infections and infestations  Lung abscess	0 0	1 (4.2%) 1 (4.2%)	0 0
Injury, poisoning and procedural complications  Electrical burn  Soft tissue injury  Spinal compression fracture  Thermal burn	7 (15.6%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 4 (8.9%)	2 (8.3%) 0 0 0 2 (8.3%)	2 (5.6%) 0 0 1 (2.8%) 1 (2.8%)
Musculoskeletal and connective tissue disorders  Epiphysiolysis  Myalgia  Pain in extremity  Rheumatoid arthritis  Scoliosis  Spinal pain  Synovitis	6 (13.3%) 1 (2.2%) 0 1 (2.2%) 1 (2.2%) 3 (6.7%) 0 0	4 (16.7%) 0 1 (4.2%) 0 1 (4.2%) 0 1 (4.2%) 1 (4.2%)	9 (25%) 1 (2.8%) 0 1 (2.8%) 2 (5.6%) 3 (8.3%) 1 (2.8%) 1 (2.8%)
Neoplasms benign, malignant and unspecified (including cysts and polyps)  Enchondromatosis  Ewing’s sarcoma  Ewing’s sarcoma metastatic  Neuroblastoma  Osteosarcoma  Osteosarcoma metastatic  Round cell liposarcoma	7 (15.6%) 0 3 (6.7%) 1 (2.2%) 1 (2.2%) 0 1 (2.2%) 1 (2.2%)	5 (20.8%) 1 (4.2%) 1 (4.2%) 0 0 3 (12.5%) 0 0	8 (22.2%) 1 (2.8%) 2 (5.6%) 1 (2.8%) 1 (2.8%) 2 (5.6%) 0 1 (2.8%)
Nervous system disorders  Burning feet syndrome  Complex regional pain syndrome  Neuralgia	4 (8.9%) 0 3 (6.7%) 1 (2.2%)	1 (4.2%) 1 (4.2%) 0 0	4 (11.1%) 1 (2.8%) 3 (8.3%) 0
Skin and subcutaneous tissue disorders  Cutaneous lupus erythematosus	0 0	1 (4.2%) 1 (4.2%)	1 (2.8%) 1 (2.8%)
Surgical and medical procedures  Bone marrow conditioning regimen  Chest wall operation  Limb operation  Lung cyst removal  Scoliosis surgery  Spinal operation  Surgery  Thoracotomy  Tumor excision	12 (26.7%) 2 (4.4%) 3 (6.7%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 2 (4.4%) 0	6 (25%) 0 1 (4.2%) 0 0 0 0 1 (4.2%) 3 (12.5%) 1 (4.2%)	4 (11.1%) 0 1 (2.8%) 1 (2.8%) 0 0 1 (2.8%) 0 0 1 (2.8%)

Note: Data are number of patients (%).

Figure 1 Patient flow chart. (A) Randomized treatment phase, (B) tapentadol extension phase, (C) safety observation.

Figure 2 Mean change in pain intensity (SD) from baseline to the last six assessments before final administration of trial medication (randomized treatment phase).

Abbreviations: FPS-R, Faces Pain Scale-Revised; VAS, visual analogue scale.

Figure 3 Forest plot of primary endpoint analysis and sensitivity analyses of the difference in treatment response between tapentadol PR and morphine PR (14-day randomized treatment period).

Note: ^aFor the Bayesian analysis, Bayesian estimate and 80% credibility interval are shown.

Abbreviations: CI, confidence interval; CRPS, complex regional pain syndrome; FPS-R, Faces Pain Scale-Revised; IMP, investigational medicinal product; ML, maximum likelihood; VAS, visual analogue scale.

Figure 4 Mean pain intensity under long-term tapentadol PR treatment (“as observed” data).

Note: Baseline was the last evaluation at or before the end of randomized treatment visit.

Abbreviations: B, baseline; FPS-R, Faces Pain Scale-Revised; VAS, visual analogue scale.

Table 3 Treatment-Emergent Adverse Event Profile During the Randomized Treatment Period (Safety Set)

	Tapentadol PR (n=45)	Morphine PR (n=24)
Any TEAE	26 (57.8%)	12 (50%)
Any serious TEAE	3 (6.7%)	1 (4.2%)
Any TEAE leading to discontinuation of trial medication	3^a (6.7%)	0
Any TEAE at least possibly related to the trial medication	12 (26.7%)	6 (25%)
Any TEAE incidence in ≥5% of patients
Gastrointestinal disorders	19 (42.2%)	9 (37.5%)
Nausea	10 (22.2%)	4 (16.7%)
Constipation	7 (15.6%)	4 (16.7%)
Vomiting	6 (13.3%)	8 (33.3%)
Abdominal pain	6 (13.3%)	0
Diarrhea	3 (6.7%)	1 (4.2%)
Abdominal pain upper	0	2 (8.3%)
Nervous system disorders	10 (22.2%)	4 (16.7%)
Headache	6 (13.3%)	3 (12.5%)
Dizziness	4 (8.9%)	0
Dysarthria	0	2 (8.3%)
Somnolence	0	2 (8.3%)
General disorders and administration site conditions	7 (15.6%)	7 (29.2%)
Pyrexia	3 (6.7%)	1 (4.2%)
Fatigue	2 (4.4%)	3 (12.5%)
Skin and subcutaneous tissue disorders	5 (11.1%)	4 (16.7%)
Pruritus	1 (2.2)	3 (12.5%)
Musculoskeletal and connective tissue disorders	4 (8.9%)	0
Back pain	3 (6.7%)	0
Renal and urinary disorders	2 (4.4%)	2 (8.3%)
Dysuria	0	2 (8.3%)

Notes: Data are number of patients (%). ^aOne of these patients had already completed the 14-day treatment and is therefore considered as a completer of the treatment period.

Abbreviation: TEAE, treatment-emergent adverse event.

Table 4 Treatment-Emergent Adverse Event Profile During the Tapentadol PR Extension Phase (Safety Set, n=36)

Any TEAE	30 (83.3%)
Any serious TEAE	13 (36.1%)
Any TEAE leading to discontinuation of trial medication	4 (11.1%)
Any TEAE at least possibly related to the trial medication	13 (36.1%)
Any TEAE incidence in ≥5% of patients
Infections and infestations	20 (55.6%)
Nasopharyngitis	5 (13.9%)
Gastrointestinal disorders	18 (50%)
Nausea	11 (30.6%)
Constipation	5 (13.9%)
Vomiting	5 (13.9%)
Abdominal pain	3 (8.3%)
Abdominal pain upper	3 (8.3%)
Diarrhea	3 (8.3%)
Toothache	2 (5.6%)
Nervous system disorders	17 (47.2%)
Headache	10 (27.8%)
Somnolence	3 (8.3%)
Dizziness	2 (5.6%)
Paresthesia	2 (5.6%)
General disorders and administration site conditions	10 (27.8%)
Pyrexia	3 (8.3%)
Fatigue	2 (5.6%)
Musculoskeletal and connective tissue disorders	9 (25%)
Back pain	5 (13.9%)
Pain in extremity	3 (8.3%)
Psychiatric disorders	9 (25%)
Nightmare	2 (5.6%)
Sleep disorder	2 (5.6%)
Skin and subcutaneous tissue disorders	8 (22.2%)
Pruritus	2 (5.6%)
Blood and lymphatic system disorders	7 (19.4%)
Anemia	3 (8.3%)
Thrombocytopenia	3 (8.3%)
Neutropenia	2 (5.6%)
Respiratory, thoracic and mediastinal disorders	7 (19.4%)
Oropharyngeal pain	4 (11.1%)
Cough	2 (5.6%)
Metabolism and nutrition disorders	2 (5.6%)
Hypokalemia	2 (5.6%)
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)	2 (5.6%)
Malignant neoplasm progression	2 (5.6%)

Note: Data are number of patients (%).

Abbreviation: TEAE, treatment-emergent adverse event.