Opioid-induced constipation in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review

Figures & data

Table 1 Study eligibility criteria and definitions of laxative sufficiency and inadequate response

OIC (criteria for confirmation of study eligibility)	• Participants who respond “yes” to the baseline question: “Since starting the opioid pain medication, have you been experiencing constipation or worsening of current constipation? Yes/No”) OR
	• Patient must report laxative use (see definition below) if the number of BMs in the past two weeks is ≥3 per week OR
	• Patients with less than three BMs per week in the past 2 weeks were eligible, regardless of whether they report laxative use OR
	• Patients who did not report laxative use but reported at least one symptom of OIC at least “moderate” or more often on the PAC-SYM screening questions in the past 2 weeks (ie, incomplete BM, BM too hard, straining during BM, or sensation of false alarm)
Laxative classesa	• Stool softeners, eg, docusate sodium (Colace^®, Ducolax^® stool softener), mineral oil
	• Osmotics, eg, polyethylene glycol 3350 (Miralax^®, Dulcolax^® balance)
	• Stimulants, eg, bisacodyl (Dulcolax^® laxative), senna (Ex-Lax^®, Senokot^®)
	• Salines, eg, magnesium hydrochloride (milk of magnesia, Citroma^®)
	• Rectal options (suppositories, enemas)
	• Prescription laxative treatments, eg, polyethylene glycol 3350, lactulose (Constulose^®), lubiprostone (Amitiza^®), methylnaltrexone bromide (Relistor^®)
Sufficient laxative use	Use of at least one laxative ≥4 times over the last 2 weeks
Insufficient laxative use	Use of laxatives less than four times but ≥1 time over the last 2 weeks
Nonlaxative use 1× LIR	No reported laxative use over the last 2 weeks
	Sufficient laxative use (use of at least one laxative agent from a class ≥4 times in the last 2 weeks) and inadequate response, defined as <3 BMs AND ≥1 PAC-SYM symptom scored moderate, severe, or very severe
2× LIR	Sufficient laxative use of agents from two different classes (use of at least two laxative agents from at least two different classes ≥4 times each in the last 2 weeks) and inadequate response, defined as <3 BMs AND ≥1 PAC-SYM symptom scored moderate, severe, or very severe

Notes:

a Participants were asked about their use of a range of behavioral interventions and therapeutic agents via a series of pictures with brand name and generic drug information provided. In order to provide a more stringent definition of inadequate response, the following classes were considered laxatives: stool softeners, stimulants, saline, rectal, and prescription laxative treatments. Probiotics, natural diet changes, increased fluids, increased exercise/activity, and OTC fiber supplements were not defined as laxatives for the purposes of defining inadequate response. However, information about utilization of these treatments is summarized in Table 5.

Abbreviations: BM, bowel movement; LIR, laxative-inadequate responders; 1× LIR, inadequate response to one laxative agent; 2× LIR, inadequate response to ≥ 2 agents from ≥2 different laxative classes; OIC, opioid-induced constipation; OTC, over-the-counter; PAC-SYM, Patient Assessment of Constipation-Symptoms.

Table 5 Summary of natural/behavioral therapies and laxative utilization by category of therapy

Use within each category (past 2 weeks)	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Natural/behavioral therapies,a n (%)
≥1	412 (83.6)	199 (82.2)	36 (94.7)	93 (80.9)	84 (85.7)
≥2	328 (66.5)	157 (64.9)	27 (71.1)	76 (66.1)	68 (69.4)
≥3	191 (38.7)	91 (37.6)	14 (36.8)	50 (43.5)	36 (36.7)
OTC laxatives,b n (%)
≥1	295 (59.8)	176 (72.7)	28 (73.7)	50 (43.5)	41 (41.8)
≥2	120 (24.3)	77 (31.8)	13 (34.2)	17 (14.8)	13 (13.3)
≥3	39 (7.9)	34 (14.0)	2 (5.3)	3 (2.6)	0 (0.0)
Prescription laxatives,c n (%)
≥1	91 (18.5)	19 (7.9)	3 (7.9)	51 (44.3)	18 (18.4)
≥2	7 (1.4)	3 (1.2)	0 (0.0)	1 (0.9)	3 (3.1)
≥3	2 (0.4)	2 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)
Natural/behavioral therapies and laxative combinations, n (%)
≥1 natural/behavioral therapies and 1 OTC only	208 (42.2)	128 (52.9)	24 (63.2)	25 (21.7)	31 (31.6)
≥1 natural/behavioral therapies only	121 (24.5)	52 (21.5)	9 (23.7)	22 (19.1)	38 (38.8)
≥1 OTC only	45 (9.1)	33 (13.6)	1 (2.6)	7 (6.1)	4 (4.1)
≥1 natural/behavioral therapies, OTC, and ≥1 prescription laxative	39 (7.9)	15 (6.2)	3 (7.9)	16 (13.9)	5 (5.1)
≥1 natural/behavioral therapies and ≥1 prescription laxative only	44 (8.9)	4 (1.7)	0 (0.0)	30 (26.1)	10 (10.2)
≥1 prescription laxatives only	5 (1.0)	0 (0.0)	0 (0.0)	3 (2.6)	2 (2.0)
≥1 prescription laxatives and OTC only	3 (0.6)	0 (0.0)	0 (0.0)	2 (1.7)	1 (1.0)
No natural/behavioral therapy or laxative use	28 (5.7)	10 (4.1)	1 (2.6)	10 (8.7)	7 (7.1)

Notes:

a Includes probiotics, natural dietary changes, increased fluids, increased exercise, and fiber supplements;

b includes stool softeners, osmotic laxatives, saline laxatives, rectal options, and other OTC products;

c includes prescription osmotic laxatives, lactulose, Amitiza^®, Relistor^®, and other prescriptions.

Abbreviation: OTC, over-the-counter.

Table 2 Patient-reported clinical characteristics and pain

	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Discussed OIC with HCP
Yes, n (%)	310 (62.9)	156 (64.5)	23 (60.5)	87 (75.7)	44 (44.9)
Health rating, n (%)
Excellent	7 (1.4)	5 (2.1)	1 (2.6)	1 (0.9)	0 (0.0)
Very good	33 (6.7)	23 (9.5)	4 (10.5)	2 (1.7)	4 (4.1)
Good	147 (29.8)	97 (40.1)	13 (34.2)	12 (10.4)	25 (25.5)
Fair	207 (42.0)	91 (37.6)	16 (42.1)	66 (57.4)	34 (34.7)
Poor	96 (19.5)	24 (9.9)	4 (10.5)	33 (28.7)	35 (35.7)
Missing	3 (0.6)	2 (0.8)	0 (0.0)	1 (0.9)	0 (0.0)
Type of chronic pain, n (%)a
Back pain	379 (76.9)	209 (86.4)	23 (60.5)	79 (68.7)	68 (69.4)
Joint pain	256 (51.9)	126 (52.1)	17 (44.7)	58 (50.4)	55 (56.1)
Fibromyalgia	74 (15.0)	29 (12.0)	14 (36.8)	20 (17.4)	11 (11.2)
Headache or migraine	80 (16.2)	48 (19.8)	5 (13.2)	15 (13.0)	12 (12.2)
Osteoarthritis	95 (19.3)	47 (19.4)	11 (28.9)	5 (4.3)	32 (32.7)
Rheumatoid arthritis	41 (8.3)	24 (9.9)	3 (7.9)	9 (7.8)	5 (5.1)
Neuralgia	115 (23.3)	48 (19.8)	14 (36.8)	31 (27.0)	22 (22.4)
Pain syndrome	163 (33.1)	21 (8.7)	6 (15.8)	83 (72.2)	53 (54.1)
Other	8 (1.6)	3 (1.2)	0 (0.0)	5 (4.3)	0 (0.0)
Pain severity
Mean pain last 24 hours (SD)	6.3 (1.8)	6.4 (1.7)	6.2 (1.9)	5.6 (1.9)	6.7 (1.8)
Mean pain last 7 days (SD)	6.3 (1.7)	6.4 (1.6)	6.3 (1.9)	5.7 (2.0)	6.9 (1.5)
How much does the constipation interfere with the ability of opioid medication to control pain? n (%)	n=461	n=235	n=37	n=98	n=91
No interference; pain adequately managed	89 (19.3)	34 (14.5)	8 (21.6)	27 (27.6)	20 (22.0)
Little interference; pain mostly managed	147 (31.9)	80 (34.0)	14 (37.8)	30 (30.6)	23 (25.3)
Moderate interference; pain moderately managed	203 (44.0)	115 (48.9)	14 (37.8)	35 (35.7)	39 (42.9)
Complete interference with adequate pain management; pain not at all managed	22 (4.8)	6 (2.6)	1 (2.7)	6 (6.1)	9 (9.9)
In the past 7 days, did you change how you used your opioid medication(s) so that you could have BMs? (n, % yes)	37 (7.5)	23 (9.5)	2 (5.3)	1 (0.9)	11 (11.2)
If yes, how did you change? (n, %)	n=37	n=23	n=2	n=1	n=11
No longer take my pain medication	1 (2.7)	0 (0.0)	0 (0.0)	0 (0.0)	1 (9.1)
Reduced how much of my pain medication I use	16 (43.2)	11 (47.8)	1 (50.0)	0 (0.0)	4 (36.4)
Temporarily interrupted the use of pain medication	18 (48.6)	14 (60.9)	0 (0.0)	0 (0.0)	4 (36.4)
Switched to a different pain medication	4 (10.8)	1 (4.3)	0 (0.0)	1 (100.0)	2 (18.2)
Other	1 (2.7)	0 (0.0)	1 (50.0)	0 (0.0)	0 (0.0)

Note:

a This category is not mutually exclusive and participants were able to report more than one type of chronic pain.

Abbreviations: BMs, bowel movements; SD, standard deviation; HCP, health care provider; OIC, opioid-induced constipation.

Table 3 Chart review of clinical characteristics

	Overall (n=482)	USA (n=237)	Canada (n=35)	Germany (n=114)	UK (n=96)
Chronic pain medications (n, %)a
Alkaloid	1 (0.2)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.0)
Anesthetic	15 (3.1)	5 (2.1)	0 (0.0)	3 (2.6)	7 (7.3)
Anticonvulsant	112 (23.2)	39 (16.5)	9 (25.7)	38 (33.3)	26 (27.1)
Antidepressant/SNRI	52 (10.8)	10 (4.2)	4 (11.4)	20 (17.5)	18 (18.8)
Barbiturate	1 (0.2)	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)
Benzodiazepine	20 (4.1)	12 (5.1)	4 (11.4)	2 (1.8)	2 (2.1)
Cannaboid/cannabinoid	2 (0.4)	0 (0.0)	1 (2.9)	0 (0.0)	1 (1.0)
Headache/migraine medication	32 (6.6)	8 (3.4)	1 (2.9)	1 (0.9)	22 (22.9)
Muscle relaxant	69 (14.3)	47 (19.8)	6 (17.1)	13 (11.4)	3 (3.1)
NSAID	80 (16.6)	31 (13.1)	3 (8.6)	23 (20.2)	23 (24.0)
Opioid	450 (93.4)	233 (98.3)	33 (94.3)	89 (78.1)	95 (99.0)
Steroid	16 (3.3)	7 (3.0)	0 (0.0)	4 (3.5)	5 (5.2)
Tricyclic antidepressant	35 (7.3)	5 (2.1)	1 (2.9)	13 (11.4)	16 (16.7)
Other pain medication	59 (12.2)	12 (5.1)	0 (0.0)	30 (26.3)	17 (17.7)
Most commonly used opioid medications (n, %)b
Codeine	36 (7.5)	1 (0.4)	2 (5.7)	0 (0.0)	33 (34.4)
Fentanyl	42 (8.7)	15 (6.3)	8 (22.9)	11 (9.6)	8 (8.3)
Hydrocodone or dihydrocodeine	75 (15.6)	69 (29.1)	0 (0.0)	0 (0.0)	6 (6.3)
Hydromorphone	31 (6.4)	6 (2.5)	3 (8.6)	22 (19.3)	0 (0.0)
Morphine	76 (15.8)	36 (15.2)	4 (11.4)	19 (16.7)	17 (17.7)
Oxycodone	201 (41.7)	134 (56.5)	22 (62.9)	31 (27.2)	14 (14.6)
Tramadol	72 (14.9)	19 (8.0)	3 (8.6)	5 (4.4)	45 (46.9)
Other opioid	68 (14.1)	25 (10.5)	2 (5.7)	32 (28.1)	9 (9.4)
Comorbid conditions (n, %)
Hypertension	133 (27.6)	62 (26.2)	11 (31.4)	34 (29.8)	26 (27.1)
Depression	79 (16.4)	30 (12.7)	6 (17.1)	16 (14.0)	27 (28.1)
Anxiety	56 (11.6)	31 (13.1)	7 (20.0)	4 (3.5)	14 (14.6)
Diabetes mellitus	48 (10.0)	24 (10.1)	5 (14.3)	9 (7.9)	10 (10.4)
Hypothyroidism	32 (6.6)	11 (4.6)	4 (11.4)	7 (6.1)	10 (10.4)
Coronary artery disease	18 (3.7)	5 (2.1)	3 (8.6)	6 (5.3)	4 (4.2)

Notes:

a Medications for chronic pain documented in chart review from most recent treatment regimen;

b opioid medications recorded in chart review with a prevalence of 5% or more.

Abbreviations: NSAID, non-steroidal anti-inflammatory drug; SNRI, serotonin-norepinephrine reuptake inhibitor.

Table 4 PAC-SYM items and subscales and additional at least moderate constipation symptoms

	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Any symptom ≥ moderate present, n (%)	481 (97.6)	239 (98.8)	35 (92.1)	110 (95.7)	97 (99.0)
Discomfort in abdomen, n (%)	316 (64.1)	157 (64.9)	22 (57.9)	62 (53.9)	75 (76.5)
Pain in abdomen, n (%)	255 (51.7)	127 (52.5)	17 (44.7)	51 (44.3)	60 (61.2)
Bloating in abdomen, n (%)	338 (68.6)	150 (62.0)	23 (60.5)	83 (72.2)	82 (83.7)
Stomach cramps, n (%)	255 (51.7)	140 (57.9)	22 (57.9)	34 (29.6)	59 (60.2)
Painful BM, n (%)	330 (66.9)	171 (70.7)	23 (60.5)	62 (53.9)	74 (75.5)
Rectal burning during or after BM, n (%)	211 (42.8)	109 (45.0)	13 (34.2)	37 (32.2)	52 (53.1)
Rectal bleeding/tearing during or after BM, n (%)	131 (26.6)	61 (25.2)	6 (15.8)	31 (27.0)	33 (33.7)
Incomplete BM, n (%)	337 (68.4)	165 (68.2)	21 (55.3)	74 (64.3)	77 (78.6)
BMs too hard, n (%)	370 (75.1)	192 (79.3)	25 (65.8)	79 (68.7)	74 (75.5)
BMs too small, n (%)	312 (63.3)	164 (67.8)	19 (50.0)	70 (60.9)	59 (60.2)
Straining/squeezing to pass BM, n (%)	407 (82.6)	202 (83.5)	28 (73.7)	89 (77.4)	88 (89.8)
Feeling like had to pass BM but could not, n (%)	295 (59.8)	145 (59.9)	20 (52.6)	63 (54.8)	67 (68.4)
Additional symptoms
Nausea, n (%)	109 (22.1)	52 (21.5)	5 (13.2)	25 (21.7)	27 (27.6)
Vomiting, n (%)	28 (5.7)	16 (6.6)	2 (5.3)	4 (3.5)	6 (6.1)
Flatulence, n (%)	341 (69.2)	168 (69.4)	23 (60.5)	77 (67.0)	73 (74.5)
Gastroesophageal reflux, n (%)	181 (36.7)	106 (43.8)	15 (39.5)	28 (24.3)	32 (32.7)
Headache or migraine, n (%)	193 (39.1)	108 (44.6)	13 (34.2)	34 (29.6)	38 (38.8)

Abbreviations: BM, bowel movement; PAC-SYM, Patient Assessment of Constipation-Symptoms.

Table 6 Sufficiency of laxative use and inadequate response to laxatives

	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Sufficient laxative usea	198 (40.2)	88 (36.4)	19 (50.0)	58 (50.4)	33 (33.7)
Insufficient laxative useb	118 (23.9)	68 (28.1)	8 (21.1)	24 (20.9)	18 (18.4)
Nonlaxative usec	177 (35.9)	86 (35.5)	11 (28.9)	33 (28.7)	47 (48.0)
LIR status last 2 weeks
1× LIR statusd	186 (93.9)	86 (97.7)	16 (84.2)	52 (89.7)	32 (97.0)
2× LIR statuse	54 (27.3)	28 (31.8)	8 (42.1)	13 (22.4)	5 (15.2)

Notes: Data are presented as n (%).

a Use of at least one laxative ≥4 times over the last 2 weeks;

b use of at least one laxative <4 times but at least once over the last 2 weeks;

c no reported laxative use over the last 2 weeks;

d sufficient laxative use (use of at least one laxative agent from a class ≥4 times in the last 2 weeks) and inadequate response, defined as <3 BMs AND ≥1 PAC-SYM scored moderate, severe, or very severe;

e sufficient use of at least two laxative agents from at least two different classes ≥4 times each in the last 2 weeks and inadequate response, defined as <3 BMs AND ≥1 PAC-SYM scored moderate, severe, or very severe.

Abbreviations: BMs, bowel movements; LIR, inadequate response to laxatives; 1× LIR, inadequate response to one laxative agent; 2× LIR, inadequate response to ≥2 agents from ≥2 different laxative classes; PAC-SYM, Patient Assessment of Constipation-Symptoms.

Table 7 WPAI-Constipation and EQ-5D

	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Are you currently employed? (n, % yes)	132 (26.8%)	81 (33.5%)	10 (26.3%)	17 (14.8%)	24 (24.5%)
If yes: during the past 7 days …
… how many hours did you miss from work because of problems associated with your constipation? (mean ± SD) hours	n=132 4.6 (11.9)	n=81 6.2 (13.9)	n=10 1.9 (4.2)	n=17 0.2 (0.8)	n=24 3.2 (10.4)
… how many hours did you miss from work because of any other reason? (mean ± SD) hours	n=132 3.0 (8.4)	n=81 1.6 (5.3)	n=10 4.5 (12.6)	n=17 2.9 (8.3)	n=24 7.0 (12.9)
… how many hours did you actually work? (mean ± SD) hours	n=132 30.8 (16.4)	n=81 36.3 (13.7)	n=10 29.8 (15.0)	n=17 27.7 (14.0)	n=24 15.0 (16.7)
WPAI-Constipation outcomes (mean %, SD)
Percent work time missed (absenteeism)a	n=120 8.9 (20.0)	n=79 10.1 (18.9)	n=9 4.8 (9.5)	n=16 0.8 (2.3)	n=16 13.1 (34.0)
Percent impairment while working (presenteeism)b	n=117 32.2 (21.9)	n=78 38.3 (21.3)	n=9 31.1 (16.9)	n=16 14.4 (14.6)	n=14 19.3 (19.0)
Percent impairment in overall work productivityc	n=117 29.0 (19.3)	n=78 33.8 (18.6)	n=9 29.2 (16.2)	n=16 14.3 (14.6)	n=14 19.0 (18.5)
Percent daily activity impairmentd	n=493 38.4 (24.4)	n=242 43.3 (22.9)	n=38 30.8 (27.8)	n=115 34.1 (26.6)	n=98 34.5 (21.9)
EQ-5D Indexe	n=449 0.49 (0.29)	n=214 0.54 (0.23)	n=28 0.61 (0.18)	n=111 0.55 (0.31)	n=96 0.27 (0.33)
EQ-5D VASf	n=446 50.6 (21.6)	n=211 52.9 (21.9)	n=26 58.6 (21.4)	n=113 45.0 (19.2)	n=96 49.9 (22.5)

Notes:

a Number of hours missed due to constipation/(number of hours missed due to constipation + number of hours missed due to other reasons);

b degree constipation affected productivity while working as reported on a 0–10 scale, where 0 was “no effect” and 10 was “completely prevented productivity”/10;

c number of hours missed due to constipation/(hours missed due to constipation + hours actually worked) + [(1 - hours missed due to constipation)/(hours missed due to constipation + hours actually worked) × (degree constipation affected productivity while working/10)];

d percent daily activity impairment refers to degree constipation affected regular activities as reported on a 0–10 scale, where 0 was “no effect” and 10 was “completely prevented activity”/10;

e country-specific weights were used to calculate scores;^25,38 the EQ-5D Index ranges from 0 (death) to 1 (full health);

f the EQ-5D VAS ranges from 0 (worst health state) to 100 (best imaginable health state).

Abbreviations: SD, standard deviation; EQ-5D, EuroQOL 5 Dimensions; VAS, visual analog scale; WPAI, Work Productivity and Activity Impairment.

Table 8 Benefit, satisfaction, and willingness to continue treatment

	Overall (n=493)	USA (n=242)	Canada (n=38)	Germany (n=115)	UK (n=98)
Have you had any benefit from your constipation treatment? n (%)
No	164 (33.3%)	79 (32.6%)	10 (26.3%)	39 (33.9%)	36 (36.7%)
Yes	329 (66.7%)	163 (67.4%)	28 (73.7%)	76 (66.1%)	62 (63.3%)
If yes, how much benefit? n (%)
Little benefit	185 (56.2%)	112 (68.7%)	15 (53.6%)	29 (38.2%)	29 (46.8%)
Much benefit	144 (43.8%)	51 (31.3%)	13 (46.4%)	47 (61.8%)	33 (53.2%)
Taking all things into account, are you satisfied with your constipation treatment? n (%)a	n=331	n=99	n=23	n=111	n=98
No	184 (55.6%)	78 (78.8%)	12 (52.2%)	42 (37.8%)	52 (53.1%)
Yes	147 (44.4%)	21 (21.2%)	11 (47.8%)	69 (62.2%)	46 (46.9%)
If yes, how satisfied? n (%)
A little satisfied	74 (50.3%)	17 (81.0%)	7 (63.6%)	29 (42.0%)	21 (45.7%)
Very satisfied	73 (49.7%)	4 (19.0%)	4 (36.4%)	40 (58.0%)	25 (54.3%)
If no, how dissatisfied? n (%)
A little dissatisfied	89 (48.4%)	32 (41.0%)	7 (58.3%)	27 (64.3%)	23 (44.2%)
Very dissatisfied	95 (51.6%)	46 (59.0%)	5 (41.7%)	15 (35.7%)	29 (55.8%)
Would you be willing to continue constipation treatment with this medication? n (%)
No	31 (6.3%)	24 (9.9%)	3 (7.9%)	2 (1.7%)	2 (2.0%)
Yes	462 (93.7%)	218 (90.1%)	35 (92.1%)	113 (98.3%)	96 (98.0%)
If yes, how willing? n (%)
A little bit willing	125 (27.1%)	77 (35.3%)	10 (28.6%)	12 (10.6%)	26 (27.1%)
Very willing	334 (72.3%)	139 (63.8%)	25 (71.4%)	100 (88.5%)	70 (72.9%)
Missing	3 (0.6%)	2 (0.9%)	0 (0.0%)	1 (0.9%)	0 (0.0%)
If no, how unwilling? n (%)
A little unwilling	22 (71.0%)	17 (70.8%)	3 (100.0%)	2 (100.0%)	0 (0.0%)
Very unwilling	9 (29.0%)	7 (29.2%)	0 (0.0%)	0 (0.0%)	2 (100.0%)

Note:

a Due to a problem with the programming of the survey, this question was not presented to 162 participants and data are missing.

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