1. Opiate use in patients with inflammatory bowel disease
Opiate use in patients with inflammatory bowel disease. Prescription trends and survival analysis in a UK primary care cohort from
Nick Burr

2. Outline Opiate epidemic Opiates in GI disease Project Conclusions
Prescriptions of opiate medications in UK IBD
Survival analyses
Conclusions

3. USA - The opiate epidemic
Okie et al, NEJM 2010

4. UK 6 fold increase in opiate prescriptions 2005-2012.
Foy et al, BMJ open 2016

5. Drug-related deaths in England: latest dataUK
Drug-related deaths in England : findings from latest ONS data – PHE 2014
Drug-related deaths in England: latest data

6. Opiates and the GI tract
Systemic problems:
Addiction
Overdose
Tachyphylaxis
Hyperalgesia
GI adverse effects
Decreased gut transit and secretions
Inhibitory effects on gastroduodenal transit
Sphincter of Oddi contraction
Narcotic bowel

7. Opiates in patients with IBD
Adverse outcomes in IBD
Mask disease symptoms
Precipitate toxic dilatation
Infections - TREAT registry (Lichtenstein, CGH 2006)
High healthcare utilisation (Click, IBD 2016)
Post operative complications (52.8% vs 40.8%; P < .001) (Li, JAMA surg 2016)
Mortality, (OR 2.82, 95 % CI 1.58 – 5.02) (Targownik, AJG 2014)
No previous UK population studies on opiate epidemiology in IBD
No studies examining outcomes in this population

8. Project objectives
Examine the trends of opiate medication prescriptions in England.
Investigate the association between different opiate medication classes and survival.

9. Project database
ResearchOne UK primary care database.
~ 6 million individuals.
Primary care entered clinical codes.
Electronic prescription data.

10. Study design Cohort Prescription density.
Patients with Read code for IBD CD UC
Opiate medications stratified:
Any opiate medication
Codeine use only
Tramadol +/- codeine
Strong opiates
Prescription density.
Never user
1-3 / year
> 3 / year

11. Propensity score Propensity score Co-variates
Match treated and untreated observations on the estimated probability of being treated.
Matched 1:1
Calipers 0.2
Nearest neighbour
Co-variates
Age at IBD diagnosis
Sex
Smoking
Duration of IBD
Year of IBD diagnosis
Index of multiple deprivation score
Charlson co-morbidity score
Use of immunomodulator therapy
Early corticosteroid use
GI surgical resection

12. Results

13. Trend in the percentage of UK primary care patients with inflammatory bowel disease receiving an opiate prescription between

14. Crohn's disease unmatched cohort
Opiate user
Opiate non-user
p-value
Number, n (%)
764 (22)
2753 (78)
Duration of follow up, median years (IQR)
9 (4 - 13)
7 (3 - 12)
<0.005
Female sex, n (%)
471 (62)
1405 (51)
Age at diagnosis, mean (sd)
48 (18)
42 (19)
Index of Multiple Deprivation Score, median (IQR)
21 ( )
19 ( )
0.11
Ever smoked, n (%)
459 (63)
1326 (51)
Gastrointestinal resection surgery, n (%)
159 (20)
363 (13)
First steroid prescription within 90 days of diagnosis, n (%)
144 (19)
487 (18)
0.46
Ever prescribed a thiopurine or methotrexate, n (%)
282 (37)
961 (35)
0.31
Charlson co-morbidity score ≥ 2, n (%)
221 (29)
436 (16)

15. Crohn's disease propensity matched cohort
Opiate user
Opiate non-user
p-value
Number, n (%)
762 (50)
Duration of follow up, median years (IQR)
9 (4 - 13)
0.53
Female sex, n (%)
470 (62)
1.00
Age at diagnosis, mean (sd)
48 (18)
49 (19)
0.58
Index of Multiple Deprivation Score, median (IQR)
21 ( )
19 ( )
0.90
Ever smoked, n (%)
457 (63)
449 (62)
0.84
Gastrointestinal resection surgery, n (%)
149 (20)
151 (20)
First steroid prescription within 90 days of diagnosis, n (%)
144 (19)
134 (18)
0.44
Ever prescribed a thiopurine or methotrexate, n (%)
281 (37)
292 (38)
0.34
Charlson co-morbidity score ≥ 2, n (%)
220 (29)
219 (29)
0.96

16. Survival analysis Crohn’s disease Ulcerative colitis
Crohn’s disease
Ulcerative colitis
Hazard ratio (95% CI)
Any opiate medication
Ever versus never
1.08 (0.82 – 1.42)
1.28 (0.99 – 1.67)
1 to 3 scripts per calendar yr versus never
0.95 (0.64 – 1.41)
0.82 (0.56 – 1.21)
>3 scripts per calendar year
1.14 (0.85 – 1.56)
1.65 (1.24 – 2.19)
Codeine only
Ever versus never prescribed
1.15 (0.67 – 1.99)
1.44 (0.88 – 2.36)
1-3 prescriptions per calendar year
1.84 (0.97 – 3.46)
0.77 (0.37 – 1.59)
>3 prescriptions per calendar year
0.77 (0.39 – 1.54)
2.08 (1.22 – 3.53)
Tramadol alone or in combination with codeine
0.78 (0.39 – 1.58)
0.70 (0.36 – 1.37)
0.81 (0.32 – 2.06)
0.42 (0.16 – 1.12)
0.76 (0.33 – 1.76)
1.06 (0.49 – 2.27)

17. Survival analysis – Strong opiates
Crohn’s disease
Ulcerative colitis
Hazard ratio (95% CI)
Strong opiates
Ever versus never prescribed
2.08 (1.19 – 3.64)
2.22 (1.29 – 3.81)
1-3 prescriptions per calendar year
1.56 (0.77 – 3.17)
1.82 (0.90 – 3.69)
>3 prescriptions per calendar year
2.57 (1.39 – 4.77)
2.46 (1.38 – 4.39)
Strong opiates versus weak opiates
Ever prescribed strong opiates versus ever prescribed weak opiate
1.96 (1.12 – 3.42)
2.61 (1.49 – 4.60)
1.56 (0.77 – 3.16)
2.14 (1.03 – 4.41)
2.29 (1.25 – 4.22)
2.90 (1.59 – 5.28)

18. Limitations Observational study.
Association only.
Increased use of electronic prescribing in the study period.
Anti-TNF data not available.
Over the counter codeine use.
Illicit use.

19. Impact Opiate use is increasing in the UK IBD population.
Tramadol shows no association.
Strong association with reduced survival:
Codeine in UC patients.
Strong opiates – CD & UC.
Dose response association.
These medications should be considered a “red flag”.
This should prompt pharmacovigilence amongst primary care prescribers and IBD physicians.

20. Acknowledgments Dr Venkat Subramanian Professor Mark Hull
Dr Chris Smith
Professor Robert West

21. Questions?
Any questions?