Poor nsaid tolerability – chronic pain

Grünenthal uses its own and third-party cookies to improve the browsing experience, offer personalized content and improve its services. We use analytics scripts which set tracking cookies. More details and information can be found in our Data Privacy Statement – please refer to this to adjust your settings for website analytics tracking (e.g. enable/disable). By closing this window you agree to our standard Terms of Use.

Poor NSAID tolerability in patients with chronic pain — what can be done?
This website is designed for healthcare professionals. Patients with chronic pain seeking treatment advice should speak to a doctor, and may also wish to access the patient resources that are freely available on the CHANGE PAIN® website

How to help your patients who report nausea with NSAIDs in chronic pain

NSAIDs are up to 40% associated with GI complications1 that include mucosal ulceration, gut inflammation, gut permeability, perforation and bleeding1, as well as GI-associated side effects that are not associated with mucosal lesions1. Upper GI tract symptoms are well documented1, however, the association with damage to the lower GI tract has not been widely studied and remains poorly characterized and are challenging to investigate1. One of the lower mortality rate estimates is from Spain, which found 15.3 deaths per 100,000 NSAID users2) (compare with 3.7 road deaths per 100,000 Spaniards3).

Find out about using weak opioids for patients with poor NSAID tolerability
Gastro-intestinal tract

Up to 40% of patients who take NSAIDs suffer upper GI tract symptoms1

Car Accident

Severe GI complications with NSAIDs can cause more fatalities than road accidents*2,3

* Data from Spain

How to help patients with chronic pain who suffering GI ulceration with NSAIDs?

NSAID-associated ulcerogenic properties are caused by the presence of COX-1 enzymes in the gastric mucosa4. Classical NSAIDs are not COX-2 selective, which means they inhibit the gastroprotective effects of COX-14.

Find out about using weak opioids for patients with poor NSAID tolerability
  • 15–30% of patients who regularly take classical NSAIDs develop GI ulcers4
  • The frequency of GI tract inflammation in patients receiving NSAIDs is 60–70%1

How can you treat chronic pain in patients with angina - how to manage CV and renal risk of NSAIDs? Jennifer’s physician is concerned about the CV and renal risk associated with NSAIDs

The use of NSAIDs carries CV6 and renal risks6 that have caused concern4, especially in elderly patients with existing CV7 or renal6,7 co-morbidities or risk factors. The European Medicines Agency has responded to these concerns by issuing guidance that NSAID use should be kept to a minimum, and that the patient’s individual risk factors should be taken into account5.

Find out about using weak opioids as an add-on or alternative to NSAIDs for patients at high CV risk

Use NSAIDs at the lowest effective dose for the shortest possible duration to control symptoms5

European Medicines Agency


Learn more about the risk of C. difficile associate diarrhea vs GI benefit of prescribing PPIs + NSAIDs combination.

Jennifer’s physician tried to alleviate GI symptoms by co-prescribing a proton pump inhibitor (PPI),
but this led to a C. diff infection

PPIs co-prescribed to reduce GI risk
Increased risk of C. diff
Possible increased risk of fractures


Co-prescribing PPIs can help to reduce the GI side effects that are associated with NSAIDs8, but does not help mitigate CV and renal risks. Furthermore, continued use of PPIs may be associated with an increased risk of Clostridium difficile–associate diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that doesn't improve9,10. Although rare, these C. difficile associated diarrhea are a serious concern because of significant risks of mortality and morbidity10. Some studies have also reported a risk of hip fracture from reduced bone mineral density in patients receiving PPIs11.

Find out about using weak opioids for patients with poor NSAID tolerability

Learn more about treatment of older patients, at higher risk of GI and cardio-renal NSAID complications7

Age is an important risk factor in GI and cardio-renal complications that are associated with NSAIDs7. In elderly patients gut physiology7 and drug metabolism7 are different as well as existing co-morbidities7. The concern for gastrointestinal bleeding in chronic NSAID users is heightened in the setting of co-administration with low-dose aspirin, often employed for cardioprotective purposes7. The American Geriatric Society now recommends that physicians should avoid prescribing NSAIDs to patients over the age of 757, and that opioids should be considered as an alternative7.

Find out more about using weak opioids in older patients

[NSAIDs should be] considered rarely, with extreme caution, in highly selected individuals7

American Geriatric Society guidelines
for pain in the elderly

Old couple on a bench

Jennifer is trapped in a vicious circle of pharmacological therapy for her chronic pain

Side effects worsen13 Dose is lowered

Dose is increased13
Efficacy of analgesia worsens13 Add- on of a different pain medicine is an alternative to increasing the dose14,15
63% of European patients with chronic pain worry about side effects of pain medicines12


The Vicious Circle is a concept that applies to patients receiving medication for chronic pain13. In the Vicious Circle, drug doses are alternately increased to provide adequate analgesia and decreased to reduce side effects13. Add-on therapy as an alternative to dose increase can provide an exit route from this vicious circle. For example, for patients receiving an NSAID, adding a nonclassical opioid, or a nonclassical opioid/paracetamol combined therapy, could be used as pain therapeutic option as demonstrated in knee OA or OA flare14,15.


1. Sostres C., Gargallo C.J., Lanas, A. Nonsteroidal anti-infl ammatory drugs and upper and lower gastrointestinal mucosal damageArthritis Research & Therapy 2013, 15(Suppl 3):S3 http://arthritisresearch.com/content/15/S3/S3.
2. Lanas, A et all.  A Nationwide Study of Mortality Associated with Hospital Admission Due to Severe Gastrointestinal Events and Those Associated with Nonsteroidal Antiinflammatory Drug Use. American Journal of Gastroenterology (2005) ISSN 0002-9270. doi: 10.1111/j.1572-0241.2005.41833.x
4. Ong, C.K.S., Lirk, P., Tan, C.H., Seymour, R.A. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. Clinical Medicine & Research (2007) 5:1,19-34.
5. European Medicines Agency, Evaluation of Medicines for Human Use. Opinion of the committee for medicinal products for human use pursuant to article 5(3) of regulation (EC) No 726/2004, For nonselective non-steroidal anti-inflammatory drugs (NSAIDs). EMEA/CHMP/410051/2006; EMEA/H/A-5.3/800.
6. Hörl, W. H. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals (2010) 3, 2291-2321. doi:10.3390/ph3072291.
7. American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. Pain Med. 2009;10(6):1062-1083. doi:10.1111/j.1526-4637.2009.00699.x.
8. Scheiman, J. M. The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage. Arthritis Research & Therapy (2013), 15: 3 :S5 http://arthritisresearch.com/content/15/S3/S5.
9. Janarthanan, S., Ditah, I., Phil, M., Adler, D., Ehrinpreis, M. Clostridium difficile -Associated Diarrhea and Proton Pump Inhibitor Therapy: A Meta-Analysis. Am J Gastroenterol 107 (2012) 1001 – 1010.


10. Oshima, T., Wu, L., Li, M. , Fukui, H., Watar, J., Miwa, H.  Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol (2017) DOI 10.1007/s00535-017-1369-3.
11. Khalili, H.,  Huang, S., Jacobson, B., Camargo, Jr C.,  Feskanich, Diane., Chan, A. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ (2012) 344 -372.
12. Breivik, H., Collett, B., Ventafridda, V., Cohen, R. & Gallacher, D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. European Journal of Pain. European Journal of Pain 10 (2006) 287–333.
13. Varrassi, G., Müller-Schwefe, G., Pergolizzi, J., Orónska, A., Morlion, B. , Mavrocordatos, P., Margarit, C.,  Mangas, C., Jaksch, W.,  Huygen, F., Collett, B., Berti, M., Aldington, D., Ahlbeck, K. Pharmacological treatment of chronic pain – the need for CHANGE. Current Medical Research and Opinion (2010)  26:5, 1231-1245.
14. Park, K., Choi, JJ., Kim, W., Min, JK., Park, SH., Cho, CS. The efficacy of tramadol/acetaminophen combination tablets (Ultracet®) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID). Clin Rheumatol (2012) 31:317–323.
15. Silverfield, J. C., Kamin, M., Wu, S.-C. & Rosenthal, N. Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Clin Ther 24, 282–297 (2002).