Non-drug pain relievers active on non-opioid pain mechanisms

Pain Pract. 2022 Feb;22(2):255-275. doi: 10.1111/papr.13073. Epub 2021 Sep 18.


This review is aimed to summarize the pain-relieving effect of non-drug substances, mostly prescribed as integrators in treatment of pain, including especially in chronic postoperative pain (CPSP) and in chronic back pain after acute episodes. Their use reflects the fact that the current treatments for these syndromes continue to pose problems of unsatisfactory responses in a significant portion of patients and/or of an excess of side effects like those noted in the present opioid crisis. As integrators are frequently introduced into the market without adequate clinical testing, this review is aimed to collect the present scientific evidence either preclinical or clinical for their effectiveness. In particular, we reviewed the data on the use of: B vitamins; vitamin C; vitamin D; alpha lipoic acid (ALA); N-acetylcysteine; acetyl L-carnitine; curcumin; boswellia serrata; magnesium; coenzyme Q10, and palmitoylethanolamide. The combination of preclinical findings and clinical observations strongly indicate that these compounds deserve more careful attention, some of them having interesting clinical potentials also in preventing chronic pain after an acute episode. In particular, examining their putative mechanisms of action it emerges that combinations of few of them may exert an extraordinary spectrum of activities on a large variety of pain-associated pathways and may be eventually used in combination with more traditional pain killers in order to extend the duration of the effect and to lower the doses. Convincing examples of effective combinations against pain are vitamin B complex plus gabapentin for CPSP, including neuropathic pain; vitamin B complex plus diclofenac against low back pain and also in association with gabapentin, and ALA for burning mouth syndrome. These as well as other examples need, however, careful controlled independent clinical studies confirming their role in therapy.

Publication types

  • Review

MeSH terms

  • Acetaminophen
  • Analgesics* / therapeutic use
  • Gabapentin / therapeutic use
  • Humans
  • Neuralgia* / drug therapy
  • Pain, Postoperative / drug therapy


  • Analgesics
  • Acetaminophen
  • Gabapentin