A comprehensive Medline, Embase and Cochrane search was performed including the following words: (“analgesics, opioid”[Pharmacological Action] OR “analgesics, opioid”[MeSH Terms] OR (“analgesics”[All Fields] AND “opioid”[All Fields]) OR “opioid analgesics”[All Fields] OR “opioid”[All Fields]) AND (“testosterone”[MeSH Terms] OR “testosterone”[All Fields]).
Publications from January 1, 1969 up to March 30, 2018 were included.
Opioids and their use in CNCP
Opioids exert their analgesic effects in humans via agonist, partial agonist or antagonist activity on opioid receptors, δ (DOP), κ (KOP) and μ (MOP) [
20]. The classical G-protein-coupled opioid receptors, known as DOP, KOP and MOP [
20], are widely distributed in the CNS and to a lesser extent in the periphery [
21]. Various endogenous ligands derived from pro-hormone precursors act at the receptors. Proenkephalin binds to DOP receptors and is cleaved to form met-enkephalin and leu-enkephalin [
22]. Dynorphin A and B, derived from prodynorphin, are agonists at the KOP receptor [
23]. Proopiomelanocortin is the precursor of β–endorphin, which has agonist activity in all three opioid receptors, but principally the MOP receptor [
24]. The nociceptin (NOP) receptor is a ‘non-classical’ G-protein-coupled receptor; its endogenous agonist is derived from a precursor compound, pre-pronociceptin. The NOP receptor is insensitive to the prototypical opioid agonist morphine and antagonist naloxone (Table
1).
Table 1
Opioid receptors with their endogenous ligands, precursors and clinical drugs with agonist or antagonist activity
Precursor | Proenkephalin | Prodynorphin | Proopiomelancortin | Pre-pronociceptin |
Peptide | Met-enkephalin, leu-enkephalin | Dynorphin A, dynorphin B | β–endorphin | N/OFQ |
Agonists |
Morphine | + | + | +++ | − |
Fentanyl | − | + | +++ | − |
Codeine | ++ | ++ | ++ | − |
Oxycodone | − | +++ | +++ | − |
Buprenorphine | − | + | ++ | + |
Tramadol | − | − | + | − |
Methadone | + | − | ++ | − |
Meperidine | + | + | ++ | − |
Tapentadol | − | + | + | − |
Antagonist |
Naloxone | ++ | ++ | +++ | − |
Opioids have been widely used for CNCP, with specific recommendations about patient selection, treatment tailoring, dose titration, maintenance therapy, and tapering doses during discontinuation [
25]. Despite some critical points, one in five US patients with CNCP receive prescription opioids [
26]. In particular, their endocrine effects can be minimized by using drugs with a lower MOP affinity.
Opioids for CNCP are commonly classified, according to their analgesic potency, as weak (codeine and tramadol) for mild-to-moderate chronic pain, or strong opioids (morphine, oxycodone, fentanyl, hydromorphone, methadone, buprenorphine, tapentadol) for severe chronic pain. They may be also classified according to their duration of action: long-acting opioids (LAO), used to maintain a stable plasma dose during chronic therapy, short-acting opioids (SAO), mainly used for titration at the beginning of opioid therapy, and rapid-onset opioids (ROO) indicated for breakthrough cancer pain.
Codeine is a pro-drug that requires metabolic conversion to morphine for analgesic activity. A small proportion of the population (5–10%) lacks the enzymes for this metabolic activation and as such are unable to derive pain relief from codeine (poor metabolizers) [
27]. It is available in fixed combination with paracetamol (acetaminophen) for mild-to-moderate pain [
28].
Tramadol is a synthetic piperidine analog of morphine. It acts as a central analgesic via MOP receptors and by modulating monoaminergic (serotonin and noradrenaline) pathways. Because its activity on the MOP receptor is significantly lower than that of morphine [
29], tramadol has less potential for respiratory depression and gastrointestinal side effects [
30,
31]. Tramadol is available in different formulations as SAO, LAO, and in association with paracetamol for mild-to-moderate chronic pain [
32,
33].
Another weak opioid is meperidine. This agent has approximately 10% of the efficacy of morphine and a half-life of only 3 h after oral administration [
34]. It is rapidly metabolized to normeperidine, which has a half-life of 8–12 h and is associated with significant CNS AEs [
34].
The strong opioid morphine has been the mainstay of chronic pain management. Morphine acts as a full agonist of the MOP receptor, with weak agonist activity at DOP and KOP receptors (Table
1) [
35]. It is commonly administered via the oral, intravenous, or intrathecal routes, but morphine has low lipid solubility, resulting in slow penetration through the blood–brain barrier [
36]. Therefore, the onset of the analgesic effect is relatively slow and the relative hydrophilicity impairs its administration through the skin. Oral bioavailability is about 30%, because morphine undergoes extensive hepatic first-pass metabolism, via glucuronidation [
37]. Morphine has been shown to significantly decrease testosterone plasma levels, probably due to the action on opioid receptors present in the testis [
17].
Oxycodone is a semi-synthetic derivative of thebaine with high oral bioavailability [
38]. The extended-release formulations provide stable plasma levels throughout the dosing interval and allow twice-daily administration [
39]. The fixed combination of oxycodone–naloxone 2:1 has significantly improved the gastrointestinal tolerability of oxycodone, reducing the incidence of opioid-induced bowel dysfunction [
40]. However, when administered in males, oxycodone significantly reduces testosterone levels; in one study, 45.5% of patients treated with oxycodone (mean 75 mg/day) had testosterone values below the normal reference range after 12 weeks of treatment [
41].
Hydromorphone is available for chronic pain management as a once-daily formulation, using an osmotic-controlled-release oral delivery system (OROS
®). This formulation is minimally affected by food or alcohol, provides stable plasma concentrations and enhances patient adherence to treatment by reducing dosing frequency [
42].
Fentanyl is a synthetic opioid analgesic with high lipid solubility and a faster onset of action than morphine [
43]. All ROOs are fentanyl based, but their use is not indicated for CNCP. In chronic pain management, fentanyl is mainly used in transdermal formulations. Compared with oral opioids, transdermal fentanyl is associated with a lower incidence of side effects (constipation, nausea and vomiting, and daytime drowsiness), increased patient satisfaction and quality of life, and improved compliance resulting from administration every 72 h [
44]. However, the convenience of the fentanyl patch should be weighed against the highest risk of androgen deficiency, when compared with other commonly prescribed opioids [
45].
The “atypical opioid” tapentadol has a pharmacological profile that is distinct from all other opioids. It has a dual mechanism of action: µ-opioid receptor agonist/noradrenaline reuptake inhibitor (MOR/NRI). The affinity of tapentadol for the MOP receptor is 50 times lower than that of morphine, which, when counterbalanced by its activity on noradrenaline modulation, results in an improved tolerability profile, lower rate of tolerance development, lower abuse potential, and efficacy in both nociceptive and neuropathic pain [
46,
47]. Tapentadol has been mainly studied in CNCP, including low back pain (LBP), neck pain, osteoarthritis, and painful diabetic peripheral neuropathy [
48‐
50]. Compared with oxycodone/naloxone, tapentadol at the mean dosage of about 378 mg/day had minimal or no significant effects on testosterone levels in male patients with severe chronic LBP [
41], probably related to the dual mechanism of action [
51].
Buprenorphine also differs from traditional opioids (pure MOP agonists), because it works as a non-selective partial opioid agonist. It produces analgesic effects via MOP receptors and also antagonizes morphine antinociception at high doses via interaction with the KOP and NOP receptors [
52]. Furthermore, compared with pure MOP agonists, buprenorphine has reduced potential for respiratory depression, overdose, and abuse, making it a useful drug for patients with chronic pain. At low dosages, transdermal buprenorphine is an accepted around-the-clock pain reliever for mild-to-moderate chronic pain [
53]. Unlike morphine, buprenorphine has only limited endocrine effects and can be used for months without inducing hypogonadism [
17].
Methadone is a synthetically derived opioid with agonist affinity for both the MOP and DOP receptors. Methadone has improved safety and tolerability compared with morphine because of its lower affinity for the MOP receptor. Methadone is mainly used in patients with chronic cancer pain who have reached a high opioid dose or in patients with a history of substance abuse as part of a methadone maintenance program (MMT) [
54]. In these patients using high-dose MMT, low serum testosterone levels have been reported: the percentage of hypogonadism in men reached 75%, while in women was only 21% [
55].