Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Mar;13 Suppl 1(s1):S4-11.
doi: 10.1111/j.1526-4637.2012.01335.x.

Preclinical pharmacology and opioid combinations

Gavril W Pasternak  1
Affiliations
Review

Preclinical pharmacology and opioid combinations

Gavril W Pasternak. Pain Med. 2012 Mar.

Abstract

Although effective alone, opioids are often used in combination with other drugs for relief of moderate to severe pain. Guidelines for acute perioperative pain recommend the use of multimodal therapy for pain management, although combinations of opioids are not specifically recommended. Mu opioid drugs include morphine, heroin, fentanyl, methadone, and morphine 6β-glucuronide (M6G). Their mechanism of action is complex, resulting in subtle pharmacological differences among them and with unpredictable differences in their potency, effectiveness, and tolerability among patients. Highly selective mu opioids do not bind to a single receptor. Rather, they interact with a large number of mu receptor subtypes with different activation profiles for the various drugs. Thus, mu-receptor-based drugs are not all the same and it may be possible to utilize these differences for enhanced pain control in a clinical setting. These differences among the drugs raise the question of whether combinations might result in better pain relief with fewer side effects. This concept has already been demonstrated between two mu opioids in preclinical studies and clinical trials on other combinations are ongoing. This article reviews the current state of knowledge about mu opioid receptor pharmacology, summarizes preclinical evidence for synergy from opioid combinations, and highlights the complex nature of the mu opioid receptor pharmacology.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structures of mu opioid analgesics.
Figure 2
Figure 2
Effect of L-methadone and morphine alone and combined with other opioids on analgesia in mice [13]. *P<0.001
Figure 2
Figure 2
Effect of L-methadone and morphine alone and combined with other opioids on analgesia in mice [13]. *P<0.001
Figure 3
Figure 3
Effect of administration of L-methadone and morphine alone and combined on analgesia and gastrointestinal transit in mice [13].
Figure 4
Figure 4
Diagram of MOR-1 (mu-opioid receptor) splicing and alternative splicing [adapted from reference 14].
Figure 4
Figure 4
Diagram of MOR-1 (mu-opioid receptor) splicing and alternative splicing [adapted from reference 14].
Figure 5
Figure 5
Analgesic activity of opioids in wildtype and knockout mice with disrupted exon 11 after administering various opioids [16]. *p<0.0001, **p<0.01
Figure 6
Figure 6
Subtle changes in receptor activation may explain subtle differences in opioid pharmacology.
See this image and copyright information in PMC

References

    1. American Society of Anesthesiologists Task Force on Acute Pain Management Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2004;100:1573–81. - PubMed
    1. Lauretti GR, Oliveira GM, Pereira NL. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003;89:2027–30. - PMC - PubMed
    1. Mercadante S, Villari P, Ferrera P, Casuccio A. Addition of a second opioid may improve opioid response in cancer pain: preliminary data. Support Care Cancer. 2004;12:762–6. - PubMed
    1. Pasternak GW. The pharmacology of mu analgesics: from patients to genes. Neuroscientist. 2001;7:220–31. - PubMed
    1. Davis MP, Pasternak . Chapter 1, Opioid receptors and opioid pharmacodynamics. In: Davis MP, Glare PA, Hardy J, Quigley C, editors. Opioids in Cancer Pain. 2nd Edition Oxford University Press; 2009.

Publication types

MeSH terms