Opioids and the Control of Respiration

Opioids and the Control of Respiration

This is a long technical article and, for even more specific details, look at the 8-page original.

Respiratory depression limits the use of opioid analgesia. Although well described clinically, the specific mechanisms of opioid action on respiratory control centres in the brain have, until recently, been less well understood.

The ultimate aim of combating opioid-induced respiratory depression would benefit patients in pain and potentially reduce deaths from opioid overdose.

The incidence of postoperative opioid-induced respiratory depression in the UK has been estimated to be approximately 1%.  

Although progression to death is very rare, the numbers of patients treated with opioids mean that respiratory depression remains an important clinical problem.

Unfortunately, medical fear of respiratory depression means that pain is often under-treated and patients experience unnecessary suffering.

In addition to humanitarian concerns,inadequate postoperative analgesia has been related to postoperative pulmonary complications

I’m heartened to see more and more medical articles pointing out the dangers of inadequate pain treatment.

Therefore, it is of paramount importance to achieve sufficient analgesia with minimal side-effects, and although this usually involves a combination of therapeutic approaches, opioids remain the backbone of therapy.

In drug addicts, respiratory depression is the major cause of death.

This article reviews the mechanisms of opioid-induced respiratory depression, from the cellular to the systems level, to highlight gaps in our current understanding, and to suggest avenues for further research. The ultimate aim of combating opioid-induced respiratory depression would benefit patients in pain, and potentially reduce deaths from opioid overdose.

Current consensus describes four classes of opioid receptor:

  1. MOP (µ),
  2. KOP (κ),
  3. DOP (δ),
  4. nociceptin/orphanin FQ peptide receptor (NOP).

The endogenous ligands for these receptors include:

  1. endorphins (MOP),
  2. enkephalins (DOP and MOP), the
  3. dynorphins (KOP), and
  4. nociceptin/orphanin FQ (NOP).

The endogenous opioid system mediates many physiological effects, including pain, respiratory control, stress responses, appetite, and thermoregulation.

In addition to their major presence on pain neurones in the central nervous system, opioid receptors are present in multiple non-respiratory sites around the body, but these are outside the scope of this review

With regard to respiration, opioid receptors are abundant in respiratory control centres that include the brainstem, but also include higher centres such as the insula, thalamus, and anterior cingulate cortex.

Opioid receptors are also located in the carotid bodies and in the vagi. Mechanosensory receptors located in the epithelial, submucosal, and muscular layers of the airways relay mechanical and sensory information from the lungs and express opioid receptors

In humans, opioids cause respiration to slow and become irregular, leading to hypercapnia and hypoxia

From Wikipedia:

  • Hypercapnia, also known as CO2 retention, hypercapnea, andhypercarbia, is a condition of abnormally elevated carbon dioxide(CO2) levels in the blood. Carbon dioxide is a gaseous product of thebody’smetabolism and is normally expelled through the lungs.
  • Hypoxia (also known as hypoxiation or anoxemia) is a condition in which the body or a region of the body is deprived of adequateoxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.

Modelling has successfully explained pharmacodynamic and pharmacokinetic interactions between CO2 and opioids on breathing

With a gradual increase in opioid levels, for example, with a constant rate infusion, progressive respiratory depression causes gradual hypercapnia that contributes to the maintenance of respiration. On the other hand, a fast rise in opioid receptor occupancy resulting from an i.v. bolus would lead to apnoea

This explains why drugs with slower receptor binding (e.g. morphine) may be safer than those that bind more quickly (e.g. alfentanil and remifentanil), despite equianalgesic effects.

Although reduced ventilatory frequency and pattern is well described with opioids, currently no human studies have fully investigated the subtle effects of opioids on respiratory rhythm.

Bailey and colleagues demonstrated, in healthy human volunteers, that morphine is likely to exert its depressant effect on the HVR by direct action in the brainstem.

The interpretation of animal and human volunteer studies in the clinical context is complicated by a number of factors. These include interspecies differences and by the fact that drug interactions, sleep, pain, genetic differences, and the stress response may also have important contributions to the ultimate respiratory output

Many drugs used in anaesthesia act to enhance opioid effects on respiratory depression. Propofol, sevoflurane, and midazolam are respiratory depressants, through agonist effects on GABA and antagonist effects on NMDA receptors, and have additive or synergistic effects on respiration when combined with opioids

Although the respiratory depressant effects of ethanol[88] and benzodiazepines are mild, the concurrent use of these drugs with opioids is usually present in drug addicts suffering fatal opioid overdose

Altered chemoreception during sleep has a profound effect upon respiration, and may be a mechanistic factor in sleep disordered breathing

there are few studies of the effects of opioids on breathing during sleep in humans.

Substance P and NK-1 receptors mediate nociception and respiration, and therefore it is not surprising that there is such a close link between pain and breathing. Indeed, in several brainstem sites, nociceptive and chemoreceptive functions converge

Pain stimulates respiration

The reversal of opioid-induced respiratory depression by pain can lead to potentially disastrous consequences when alternative analgesic techniques are introduced and highlights the balance between pain and breathing in clinical situations.

This is particularly important, in clinical situations where a patient has received opioids, remains in pain (but still breathing), with subsequent neuraxial block causing severe respiratory depression.

Human studies 

In humans, interindividual variability in response to opioids may be explained by genetic factors that include sex differences, polymorphisms affecting MOP receptor activity, bioavailability, and metabolism of opioids.

In most cases, respiratory and analgesic effects change in parallel, and only one study suggests a potential genetic basis for differential respiratory and analgesic effects.

Initial studies suggested that women derive greater analgesia from opioids than do men, whereas more recent studies found no differences

Only three, relatively small studies have specifically examined sex differences in opioid-induced respiratory depression and each observed a greater respiratory depressant effect in women than in men.

Polymorphisms of the cytochrome P450 enzymes (CYP2D6) have strong effects on the metabolism of codeine and tramadol.

Many studies in humans have compared the respiratory effects of different opioids, including comparisons of drugs with differing potencies, durations of action, partial agonists, and opioids with effects on other receptor systems.

Two drugs of particular interest are tramadol and buprenorphine which appear to have differential analgesic and respiratory effects.

Human studies suggest tramadol causes less respiratory depression than meperidine or oxycodone at approximately equianalgesic doses.

The utility of tramadol is limited by its weak to moderate analgesic effect and is contraindicated in epilepsy and renal failur

reports suggest that buprenorphine is associated with fewer fatalities than methadonewhen used in the treatment of heroin addicts. It is unclear what specific cellular mechanisms account for the beneficial respiratory profile of buprenorphine.

Opioids depress respiration by a number of mechanisms and neuronal sites of action. It is therefore not surprising that there has been such difficulty in combating opioid-induced respiratory depression

The differential effects on rhythm generation and chemoreception suggest that there are many potential therapeutic targets with differing neuronal functions.


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