Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction. In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls". As a result, older adults taking opioids are at greater risk for injury. Opioids do not cause any specific organ toxicity, unlike many other drugs, such as
aspirin and paracetamol. They are not associated with upper
gastrointestinal bleeding and
kidney toxicity. Prescription of opioids for acute low back pain and management of
osteoarthritis seem to have long-term adverse effects According to the
USCDC, methadone was involved in 31% of opioid related deaths in the US between 1999–2010 and 40% as the sole drug involved, far higher than other opioids. Studies of long term opioids have found that many stop them, and that minor side effects were common. Addiction occurred in about 0.3%.
Reinforcement disorders Tolerance Tolerance is a process characterized by
neuroadaptations that result in reduced drug effects. While
receptor upregulation may often play an important role other mechanisms are also known. Tolerance is more pronounced for some effects than for others; tolerance occurs slowly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more quickly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or
miosis (the constriction of the pupil of the eye to less than or equal to two millimeters). This idea has been challenged, however, with some authors arguing that tolerance
does develop to miosis. Tolerance to opioids is attenuated by a number of substances, including: •
calcium channel blockers •
intrathecal magnesium and
zinc •
NMDA antagonists, such as
dextromethorphan,
ketamine, and
memantine. •
cholecystokinin antagonists, such as
proglumide • Newer agents such as the
phosphodiesterase inhibitor ibudilast have also been researched for this application. Tolerance is a physiologic process where the body adjusts to a medication that is frequently present, usually requiring higher doses of the same medication over time to achieve the same effect. It is a common occurrence in individuals taking high doses of opioids for extended periods, but does not predict any relationship to misuse or addiction.
Physical dependence Physical dependence is the physiological adaptation of the body to the presence of a substance, in this case opioid medication. It is defined by the development of withdrawal symptoms when the substance is discontinued, when the dose is reduced abruptly or, specifically in the case of opioids, when an antagonist (
e.g.,
naloxone) or an agonist-antagonist (
e.g.,
pentazocine) is administered. Physical dependence is a normal and expected aspect of certain medications and does not necessarily imply that the patient is addicted. The withdrawal symptoms for opiates may include severe
dysphoria, craving for another opiate dose, irritability,
sweating,
nausea,
rhinorrea,
tremor, vomiting and
myalgia. Slowly reducing the intake of opioids over days and weeks can reduce or eliminate the withdrawal symptoms. Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance. While there are anecdotal claims of benefit with
ibogaine, data to support its use in substance dependence is poor. Critical patients who received regular doses of opioids experience iatrogenic withdrawal as a frequent syndrome.
Addiction Drug addiction is a complex set of behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages. Addiction includes psychological compulsion, to the extent that the affected person persists in actions leading to dangerous or unhealthy outcomes. Opioid addiction includes
insufflation or injection, rather than taking opioids orally as prescribed for medical reasons. The amount of evidence available only permits making a weak conclusion, but it suggests that a physician properly managing opioid use in patients with no history of
substance use disorder can give long-term pain relief with little risk of developing addiction, or other serious side effects. • Some people find that opioids side effects cause problems which outweigh the therapy's benefit. All of the opioids can cause side effects. Common adverse reactions in patients taking opioids for pain relief include
nausea and vomiting,
drowsiness, itching, dry mouth,
dizziness, and
constipation.
Nausea and vomiting Tolerance to
nausea occurs within 7–10 days, during which antiemetics (
e.g. low dose
haloperidol once at night) are very effective. Due to severe side effects such as tardive dyskinesia, haloperidol is now rarely used. A related drug,
prochlorperazine is more often used, although it has similar risks. Stronger antiemetics such as
ondansetron or
tropisetron are sometimes used when nausea is severe or continuous and disturbing, despite their greater cost. A less expensive alternative is dopamine antagonists such as domperidone and metoclopramide.
Domperidone does not cross the
blood–brain barrier and produce adverse central antidopaminergic effects, but blocks opioid emetic action in the
chemoreceptor trigger zone. This drug is not available in the U.S. Some antihistamines with
anticholinergic properties (e.g.
orphenadrine,
diphenhydramine) may also be effective. The first-generation antihistamine
hydroxyzine is commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties.
THC relieves nausea and vomiting; it also produces analgesia that may allow lower doses of opioids with reduced nausea and vomiting. • 5-HT3 antagonists (
e.g. ondansetron) • Dopamine antagonists (
e.g. domperidone) • Anti-cholinergic antihistamines (
e.g. diphenhydramine) • Δ9-tetrahydrocannabinol (
e.g. dronabinol) Vomiting is due to
gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on the
chemoreceptor trigger zone of the
area postrema, the vomiting centre of the brain. Vomiting can thus be prevented by prokinetic agents (
e.g. domperidone or
metoclopramide). If vomiting has already started, these drugs need to be administered by a non-oral route (
e.g. subcutaneous for metoclopramide, rectally for domperidone). • Prokinetic agents (
e.g. domperidone) • Anti-cholinergic agents (
e.g. orphenadrine) Evidence suggests that opioid-inclusive anaesthesia is associated with postoperative nausea and vomiting. Patients with chronic pain using opioids had small improvements in pain and physically functioning and increased risk of vomiting.
Drowsiness Tolerance to
drowsiness usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as
fentanyl,
morphine and
diamorphine (heroin) tend to be particularly sedating, while others such as
oxycodone,
codeine, and
tilidine tend to produce comparatively less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Otherwise, treatment with
CNS stimulants is generally effective. • Stimulants (
e.g. caffeine,
modafinil,
amphetamine,
methylphenidate)
Itching Itching tends not to be a severe problem when opioids are used for pain relief, but
antihistamines are useful for counteracting itching when it occurs. Non-sedating antihistamines such as fexofenadine are often preferred as they avoid increasing opioid induced drowsiness. However, some sedating antihistamines such as
orphenadrine can produce a synergistic pain relieving effect permitting smaller doses of opioids be used. Consequently, several opioid/antihistamine combination products have been marketed, such as
Meprozine (
meperidine/
promethazine) and
Diconal (
dipipanone/
cyclizine), and these may also reduce opioid induced nausea. • Antihistamines (
e.g. fexofenadine)
Constipation Opioid-induced
constipation (OIC) develops in 90 to 95% of people taking opioids long-term. Since tolerance to this problem does not generally develop, most people on long-term opioids need to take a
laxative and/or
enemas. Treatment of OIC is successional and dependent on severity. The first mode of treatment is non-pharmacological, and includes lifestyle modifications like increasing
dietary fiber,
fluid intake (around per day), and
physical activity.
Osmotic laxatives, including
lactulose,
polyethylene glycol, and
milk of magnesia (magnesium hydroxide), as well as
mineral oil (a
lubricant laxative), are also commonly used for OIC. opioid formulations or regimens that include a peripherally-selective
opioid antagonist, such as
methylnaltrexone bromide,
naloxegol,
alvimopan, or
naloxone (as in
oxycodone/naloxone), may be tried. A 2018 (updated in 2022) Cochrane review found that the evidence was moderate for alvimopan, naloxone, or methylnaltrexone bromide but with increased risk of adverse events. Naloxone by mouth appears to be the most effective. A daily 0.2 mg dose of naldemedine has been shown to significantly improve symptoms in patients with OIC.
Opioid rotation is one method suggested to minimise the impact of constipation in long-term users. While all opioids cause constipation, there are some differences between drugs, with studies suggesting
tramadol,
tapentadol,
methadone and
fentanyl may cause relatively less constipation, while with
codeine,
morphine,
oxycodone or
hydromorphone constipation may be comparatively more severe.
Respiratory depression Respiratory depression is the most serious adverse reaction associated with opioid use, but it usually is seen with the use of a single, intravenous dose in an opioid-naïve patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can partially block respiratory depression, although the only respiratory stimulant currently approved for this purpose is
doxapram, which has only limited efficacy in this application. Newer drugs such as
BIMU-8 and
CX-546 may be much more effective. • Respiratory stimulants:
carotid chemoreceptor agonists (
e.g. doxapram),
5-HT4 agonists (
e.g. BIMU8), δ-opioid agonists (
e.g. BW373U86) and AMPAkines (
e.g. CX717) can all reduce respiratory depression caused by opioids without affecting analgesia, but most of these drugs are only moderately effective or have side effects which preclude use in humans. 5-HT1A agonists such as
8-OH-DPAT and
repinotan also counteract opioid-induced respiratory depression, but at the same time reduce analgesia, which limits their usefulness for this application. • Opioid antagonists (
e.g. naloxone,
nalmefene,
diprenorphine) The initial 24 hours after opioid administration appear to be the most critical with regard to life-threatening OIRD, but may be preventable with a more cautious approach to opioid use. Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD.
Increased pain sensitivity Opioid-induced hyperalgesia – where individuals using opioids to relieve pain
paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving
palliative care, most often when dose is increased rapidly. If encountered, rotation between several different opioid pain medications may decrease the development of
increased pain. Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses, but some research suggests that it may also occur with small doses. Side effects such as hyperalgesia and
allodynia, sometimes accompanied by a worsening of
neuropathic pain, may be consequences of long-term treatment with opioid analgesics, especially when increasing tolerance has resulted in loss of efficacy and consequent progressive dose escalation over time. This appears to largely be a result of actions of opioid drugs at targets other than the three classic opioid receptors, including the
nociceptin receptor,
sigma receptor and
Toll-like receptor 4, and can be counteracted in animal models by antagonists at these targets such as
J-113,397,
BD-1047 or
(+)-naloxone respectively. No drugs are currently approved specifically for counteracting opioid-induced hyperalgesia in humans and in severe cases the only solution may be to discontinue use of opioid analgesics and replace them with non-opioid analgesic drugs. However, since individual sensitivity to the development of this side effect is highly dose dependent and may vary depending which opioid analgesic is used, many patients can avoid this side effect simply through dose reduction of the opioid drug (usually accompanied by the addition of a supplemental non-opioid analgesic),
rotating between different opioid drugs, or by switching to a milder opioid with a mixed mode of action that also counteracts neuropathic pain, particularly
tramadol or
tapentadol. •
NMDA receptor antagonists such as
ketamine •
SNRIs such as
milnacipran •
Anticonvulsants such as
gabapentin or
pregabalin Other adverse effects Low sex hormone levels Clinical studies have consistently associated medical and recreational opioid use with
hypogonadism (low
sex hormone levels) in different sexes. The effect is
dose-dependent. Most studies suggest that the majority (perhaps as much as 90%) of chronic opioid users develop hypogonadism. A 2015
systematic review and
meta-analysis found that opioid therapy suppressed testosterone levels in men by about 165 ng/dL (5.7 nmol/L) on average, which was a reduction in testosterone level of almost 50%. Conversely, opioid therapy did not significantly affect testosterone levels in women. One study found that the depressed
testosterone levels of heroin addicts returned to normal within one month of abstinence, suggesting that the effect is readily reversible and is not permanent. , the effect of low-dose or acute opioid use on the
endocrine system is
unclear. Long-term use of opioids can affect the other
hormonal systems as well. Persons performing any safety-sensitive task should not use opioids. Health care providers should not recommend that workers who
drive or use
heavy equipment including
cranes or
forklifts treat chronic or acute pain with opioids. Taking opioids may further disrupt the patient's life and the adverse effects of opioids themselves can become a significant barrier to patients having an active life, gaining employment, and sustaining a career. In addition, lack of employment may be a predictor of aberrant use of prescription opioids.
Increased accident-proneness Opioid use may increase
accident-proneness. Opioids may increase risk of traffic accidents and
accidental falls.
Reduced Attention Opioids have been shown to reduce attention, more so when used with antidepressants and/or anticonvulsants.
Rare side effects Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more
potent opioids), confusion,
hallucinations,
delirium,
urticaria,
hypothermia,
bradycardia/
tachycardia,
orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). Both therapeutic and chronic use of opioids can compromise the function of the
immune system. Opioids decrease the proliferation of
macrophage progenitor cells and
lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit
leukocyte migration. However the relevance of this in the context of pain relief is not known.
Pregnancy == Interactions ==