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Review
. 2021 Oct 27;14(11):1091.
doi: 10.3390/ph14111091.

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Alok K Paul  1 , Craig M Smith  2 , Mohammed Rahmatullah  3 , Veeranoot Nissapatorn  4 , Polrat Wilairatana  5 , Mariana Spetea  6 , Nuri Gueven  1 , Nikolas Dietis  7
Affiliations
Review

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Alok K Paul et al. Pharmaceuticals (Basel). .

Abstract

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain.

Keywords: adverse effects; analgesia; behaviour; chronic pain; morphine; opioids; tolerance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of opioid agonists on pain and signal transduction. Abbreviations: ATP, adenosine triphosphate; ADP, adenosine diphosphate; GABA, gamma-aminobutyric acid; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CRE, cAMP-responsive element; CREB, cAMP-responsive element binding protein; GTP, Guanosine triphosphate; GDP, Guanosine diphosphate; PDEs, Cyclic nucleotide phosphodiesterases; Ca2+/CaMK-II, Ca2+/calmodulin-dependent protein kinase II. Symbols: solid arrow, strong activation; dashed arrow, moderate activation; solid T-shaped line, strong inhibition; dashed T-shaped line, moderate inhibition, line with ×, blocking; upward arrow, increased effect; downward arrow, decreased effect. The figure was made with www.biorender.com (accessed on 19 October 2021).
Figure 2
Figure 2
Effects of opioids on motor behaviour. Abbreviations: GABA, gamma-aminobutyric; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CRE, cAMP-responsive element; CREB, cAMP-responsive element binding protein; D1, dopamine receptor-1; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of 32 kDa; NMDA, N-methyl-D-aspartate receptor; PDEs, Cyclic nucleotide phosphodiesterases; NA, noradrenaline, VTA, ventral tegmental area; NAc, nucleus accumbens. Symbols: solid arrow, strong activation; dashed arrow, moderate activation; solid T-shaped line, strong inhibition; dashed T-shaped line, moderate inhibition, upward arrow, increased effect; downward arrow, decreased effect. The figure was made with www.biorender.com (accessed on 19 October 2021).
Figure 3
Figure 3
Effects of opioids in the gastrointestinal tract. Abbreviations: 5-HT, serotonin; GI, gastrointestinal. Symbols: solid arrow, strongly connected; dashed arrow, moderately connected; upward arrow (symbol), increased effect; downward arrow (symbol), decreased effect. The figure was made with www.biorender.com (accessed on 19 October 2021).
Figure 4
Figure 4
Effects of opioids on the respiratory function. Abbreviations: 5-HT, serotonin; GlyRα3, glycine receptor type-α3. Symbols: solid arrow, strongly connected; dashed arrow, moderately connected; upward arrow (symbol), increased effect; downward arrow (symbol), decreased effect. The figure was made with www.biorender.com (accessed on 19 October 2021).
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