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Understanding opioids.

OPIOIDS ARE among the oldest of medicines. Opium, its derivatives and synthetic analogues have been the subjects of addiction and abuse for centuries, culminating in the current epidemic of addiction in North America.

Nevertheless, modern medicine and chemistry have yet to discover a more potent form of analgesia, and morphine remains the gold standard against which all other analgesics are measured.

Aside from addiction, opioids carry significant risks for patients, even at therapeutic doses, that require careful nursing care to detect and treat.

INTRODUCTION

North America is experiencing an epidemic of prescription opioid misuse which has resulted in more than 52,000 deaths in 2017. (1,2) The United States (US) has an astonishing rate of opioid prescribing--50,000 standard daily doses for every one million of the population. In contrast, Canada (the next highest consumer) has 30,000, Australia about 20,00 and New Zealand and Great Britain about 12,000. (3)

International concern over misuse of prescription opioids, and policies to limit this, must not override the real need for opioids to manage moderate to severe pain. In 2010, it was estimated that 66 per cent of the world's population had no access to opioid analgesia, and only 7.5 per cent, exclusively in high-income nations, had adequate access. Barriers to adequate access include highly restrictive legislation due to fear of diversion or abuse, and limited education of health professionals about appropriate use. (4)

In New Zealand, the available strong opioids are morphine, pethidine, fentanyl, oxycodone and methadone. Prescription opioid use has been creeping upwards, despite awareness campaigns about harms and the inadequacy of opioids for managing chronic pain. (5) A prescription for a strong opioid most commonly follows a hospital event. Two-thirds of these are for morphine. Oxycodone use has decreased since 2012 but fentanyl use has increased. Prescribing of both these drugs varies widely between DHBs. (6) Of people receiving a strong opioid, 12.5 per cent were prescribed for six weeks or longer. (6)

Opium is the juice extracted from seeds of Papaver somniferum (the common garden poppy). Opiates are the isolated active ingredients of opium, or drugs derived from this source, eg morphine, codeine, thebaine and heroin. The term "opioid" refers to all drugs that act primarily on opioid receptors in the body, including synthetic drugs--those containing no natural opium derivatives.

MECHANISMS OF ACTION

Opioid receptors are found throughout the central nervous system (CNS), including the spinal cord. They are also found in the gastrointestinal (GI) tract and in peripheral tissues, associated with nociceptors (pain receptors). There are three main groups of opioid receptors: mu, delta and kappa. These are all cell membrane receptors--found on the surface of target cells--where activation prevents the transmission of pain signals along neural pathways.

Opioids and endorphins also trigger signalling cascades in their target cells that cause long-term changes when there is prolonged stimulation of pain pathways. These pathways probably account for the tolerance and physical dependence that accompany opioid use. (8)

Opioids and pain

Nociception--the sensory process leading to the perception of pain--begins with stimulation of pain receptors in the tissues (see Figure 1, p22). Electrical nerve impulses (action potentials) travel from the pain receptors to the dorsal horn of the spinal cord. From here, they travel via neurons to the brain and generate an awareness of pain. Pain signals arriving in the brain trigger descending inhibitory impulses which travel back down the spinal cord. These suppress transmission of pain signals. The spinal cord is the site of sophisticated processing of pain signals, where other sensory inputs can enhance, alter or inhibit pain perception, and where prolonged activation can generate structural changes leading to chronic or abnormal pain. (10)

Within the nociceptor pathway, the role of opioid analgesics is complex (see Figure 1). Opioid receptors are found in pain receptor endings. Inflammatory cells release endogenous opioids to inhibit their activation. In the spinal cord, opioid receptors are found in both presynaptic neurons, where they inhibit the release of neurotransmitters, and post-synaptic neurons--where they prevent action potentials from being triggered. In the brain, opioids produce euphoria and a sense of well-being, reducing unpleasant emotions associated with pain, and activate pain inhibition.

Drug effectiveness

The analgesic effect of opioid drugs depends on a variety of factors:

* The ability of the drug to bind to, and activate, opioid receptors.

* The structure and functional state of receptors.

* The individual's processing of the drug in the body--pharmacokinetics.

How strongly an opioid provides analgesia is determined by its ability to bind to receptors (affinity) and activate them (efficacy). Morphine binds strongly to mu receptors (high affinity) and strongly activates them (high efficacy). In contrast, codeine has high affinity for mu, but weak efficacy. Naloxone, an opioid antagonist, binds very strongly to mu receptors (high affinity) but does not activate them (zero efficacy). (8)

The variable affinity and efficacy of different agonist drugs, and between different people, may be due to genetic variations in the structure, location and number of binding sites in the opioid receptors. Opioid receptors can also alter their states, joining other receptors to change their binding and activation properties. (12) This means no one opioid drug fits all and opioid rotation may be necessary for some people until adequate analgesia is attained.

PHARMACOKINETICS

The absorption, distribution, metabolism and excretion of a drug involve complex processes that have an impact on its therapeutic effect. Opioids can be administered orally or via parenteral routes such as intravenous (IV), intramuscular (IM), subcutaneous, or epidural injection, or transdermally. The amount of drug that reaches general circulation depends on the route of administration.

Morphine

Morphine is given orally (PO) in doses far higher than are required with IV administration. The reason is that absorption of morphine from the GI tract is erratic and, once absorbed, it undergoes significant first-pass metabolism in the liver before reaching the general circulation. Thus, only a proportion of the PO dose will actually reach the site of action in its active form. This is true for most morphine-derived drugs. (8)

Morphine is converted to two main metabolites in the liver (see Figure 2, p23). The drug is joined with a glucuronide molecule to allow excretion in the kidneys. This link can occur in one of two places on the morphine molecule. Morphine-3-glucuronide has no analgesic effect, but morphine-6-glucuronide is an active metabolite and is more potent than morphine as an analgesic. High levels of morphine-3-glucuronide may cause seizures and abnormal pain, such as hyperalgesia. (13)

Morphine is contraindicated in the very young, as their immature livers cannot conjugate and inactivate the drug. They are also more prone to respiratory depression, since the immature blood-brain barrier in neonates allows easy passage of morphine into the CNS.

Codeine

Codeine is a weak agonist of the mu receptor, but exerts most of its analgesic effect because about 10 per cent is converted to morphine in the liver via Phase I metabolism (see Figure 2). Phase I metabolism involves a family of enzymes with a wide genetic variability. Some people are ultra-rapid metabolisers. Their enzymes rapidly process codeine to morphine, so good analgesia is achieved. There is a risk to children and breast-fed infants of morphine overdose if ultra-rapid metabolising occurs. For this reason, codeine or codeine-containing products are no longer approved for breastfeeding mothers and children under 12 years. (14,15) About 10 per cent of Europeans are ultra-rapid metabolisers, three to four per cent of Africans, one to two per cent of East Asians and more than 10 per cent of Pacific, Maori, Northern African, Middle Eastern populations and their genetic descendants. (16) Poor metabolisers (occurring most frequently in Europeans at five to 10 per cent of the population) may convert little codeine, so for them this drug is an ineffective form of analgesia. (8)

Diamorphine

Diamorphine (heroin) is converted to morphine and monoacetylmorphine (MAM) by Phase I metabolism (see Figure 2). Diamorphine and MAM are more lipid-soluble than morphine, so enter the CNS easily and rapidly. (17) It is this greater solubiLity that causes the "rush" following IV injection.

Synthetic opioids

While chemically similar to opiates, synthetic opioids contain no naturally occurring poppy derivatives.

Pethidine

Pethidine has an active metabolite--norpethidine --with a prolonged half-life that stays in the body up to four times longer than the active pethidine. Norpethidine has excitatory effects and can cause agitation, seizures and hallucinations if it accumulates due to repeated dosing of pethidine, especially where kidneys are impaired.

Pethidine is the most commonly used opioid worldwide for intrapartum analgesia, but may delay successful establishment of breastfeeding post-partum. (19)

Fentanyl

Fentanyl is a strong agonist of mu receptors and, being highly lipid-soluble, penetrates the CNS rapidly. Thus, it has a very rapid onset of action, requires only small doses, and is useful for sedation and treating acute pain. Due to high first-pass metabolism, routes of administration are usually parenteral, including via transdermal patch and sublingual tablets or lollipops.

Illicitly-manufactured fentanyl and its analogues are mixed with heroin, cocaine and benzodiazepines to cut production costs in illicit drug-supply chains. (2) Fentanyl's very high affinity for mu receptors, especially in the respiratory centres of the brain, high lipid-solubility and narrow therapeutic window (the difference between therapeutic and lethal doses) make it dangerous for both drug users and emergency personnel responding to drug overdose incidents, who can absorb dangerous amounts through skin contact. (1)

Methadone

Methadone is a longer-acting drug than morphine, with a similar level of agonist activity on the mu receptor. This makes it useful for managing withdrawal syndrome in addicts--abstinence syndrome has a slower onset and is less severe but lasts longer. (8) It also causes less euphoria and drowsiness than morphine.

Tramadol

Tramadol is a weak mu-receptor agonist, but has an additional analgesic mechanism: it inhibits the reuptake of noradrenaline and serotonin in the descending inhibitory pain pathway, which enhances inhibition of pain in the spinal cord.

Tramadol is metabolised by the same liver enzyme system as codeine, to become a much stronger mu-agonist. As with codeine, ultra-rapid metabolisers get very good analgesia from this drug, while poor metabolisers may get very little. Caution must be taken to ensure ultra-rapid metabolisers are not put at risk of overdose. (8)

Thebaine derivatives

Thebaine is extracted from opium along with morphine and codeine. Drugs derived from thebaine include oxycodone, buprenorphine and naloxone.

Oxycodone

Oxycodone was synthesised in 1916, but it wasn't until Perdue Pharma introduced OxyContin to the market in the mid1990s that the drug became popular. The drug was marketed as having less stigma than morphine (thus more acceptable to patients for managing chronic pain) and having less than one per cent risk of addiction. In fact, the drug is twice as potent as morphine, although not superior as an analgesic, and has a higher potential for addiction. This adverse data was not mentioned in the extraordinarily successful marketing campaign. The company has subsequently been heavily fined but continues aggressive marketing outside the US. (21,22) Given its high cost and similar effectiveness to morphine, oxycodone is recommended only where a person is intolerant to morphine. (23)

Buprenorphine

Buprenorphine is a partial agonist at the mu receptor, but binds to it strongly. This means it is slow to dissociate from the receptor, leading to prolonged action in the body. The majority of buprenorphine metabolites are excreted in the bile, so it can be used where there is poor renal function. (8)

Naloxone

Naloxone is a competitive antagonist for all three opioid receptors, preventing the binding of opioid agonist drugs. It is used to reverse opioid-induced respiratory depression. Higher doses of naloxone are required where the drug being reversed has a high affinity for opioid receptors. Onset of action is rapid, but the half-life of naloxone is only two to four hours, meaning repeat doses may be required. (8) Also, naloxone eliminates the analgesic effects of opioids so, in accidental overdose, alternative analgesia must be considered, and habitual users may suffer withdrawal symptoms.

Opioid drugs and older adults

Eleven per cent of people over 80 years of age, mainly those living in residential care, received strong opioid analgesics in New Zealand in 2016. (6)

Older adults are more susceptible to the actions of opioids, due to changes in the function of both receptors and the blood-brain barrier. They are also more vulnerable to adverse effects, due to reduced functional capacity and the presence of co-morbidities. Declining liver and renal function can lead to opioid drugs exhibiting longer half-lives, higher concentrations and prolonged activity.

ADVERSE EFFECTS

Many adverse effects of opioids are dose-related. Tolerance to some adverse effects occurs rapidly with continued treatment, but for other adverse effects, eg constipation, tolerance never occurs.

Respiratory depression

Opioid-induced respiratory depression (OIRD) is the most dangerous adverse effect of opioids and will occur at therapeutic doses.

Mu-opioid receptors are found throughout respiratory control pathways. Opioids affect the respiratory rhythm centres of the brainstem, causing slower and irregular respirations, which become increasingly shallow as opioid receptor activation increases. Opioids also inhibit chemoreceptors in the brainstem, impairing responses to decreasing oxygen and increasing carbon dioxide (C[O.sub.2]) in the plasma. As hypoventilation increases and C[O.sub.2] accumulates (hypercapnia), respiratory acidosis develops, causing cardiovascular abnormalities, CNS damage, and eventually cardio-respiratory arrest. (24)

The development of respiratory depression often follows a typical pattern:

* Reduced frequency of respirations, or changed pattern, with a slight increase in tidal volume.

* Reduced respirations (rate and depth) that can be stimulated by external stimuli, eg pain, noise and bright lights.

* Absent respirations that can be initiated on command.

* Complete apnoea.

Highest risk for OIRD is in the first 24 hours after administration, although people receiving intrathecal or spinal opioids may experience delayed effects. Increasing drug dose may also cause OIRD. While the main risk is death or brain injury, mild respiratory depression in post-operative patients, or those with underlying respiratory disease, increases risk for atalectasis or pneumonia.

Conversely, fear of respiratory failure can lead to ineffective pain management, so nurses must understand the need for thorough respiratory assessment.

Assessing OIRD

Hypoventilation may occur even where respiratory rate and breathing pattern appear normal. (27) Therefore, respiratory rate is not a reliable indicator of OIRD: a respiratory rate of less than 12 breaths per minute indicates respiratory depression, but a rate greater than 12 does not signify its absence. Nurses are notoriously poor at performing respiratory assessments conscientiously. (28)

Pulse oximetry cannot reliably detect OIRD because oxygen levels can remain high while C[O.sub.2] accumulates--especially if the patient is receiving oxygen therapy. (29) In addition, the act of applying the oximeter probe may rouse a patient sufficiently to take some deep breaths, so hypoxia could be missed. If pulse oximetry is used, continuous rather than intermittent monitoring is desirable.

Sedation scores, if used consistently, can give an early indication of respiratory failure, since sedation generally precedes other signs. (29) These assess a continuum of sedation from "awake and alert" to unrousable. A level of sedation beyond "sleeping and easily roused" is an indication of increasing sedation.

Patients must be woken overnight to check sedation scores during the first 24 hours of opioid therapy. Stable patients receiving stable opioid doses (after 24 hours) may have a respiratory assessment performed without rousing to check sedation, but if there is any indication that their sleep is not natural, further action should be taken.

Factors that increase risk of sedation and respiratory failure include: (30)

* Presence of other sedating agents (eg benzodiazepines, general anaesthesia, alcohol, history of opioid use).

* The very old and very young.

* Extremes of weight.

* Renal, liver or cardiac disease.

* History of sleep apnoea (may be undiagnosed).

* Impaired respiratory function/COPD.

* Impaired CNS function or diabetes.

For patients having single or PRN (as required) doses of opioids, it makes sense to assess for respiratory (and analgesic) effects when the peak action of the drug occurs:

* 15-30 minutes after IV administration.

* 30-40 minutes after intramuscular injection.

* 60-90 minutes after P0 dose, including sustained/prolonged release formulations.

Constipation

Binding of opioids to the mu receptors in the GI tract leads to sustained contraction of smooth muscle along the tract. This reduces peristalsis and thus movement through the bowel and impairs anal sphincter relaxation. There is also decreased secretion into the bowel, causing hard dry stools. (31)

Constipation occurs in 40-95 per cent of people taking opioids long term. This can lead to bowel obstruction; less critically, it reduces quality of life, and may lead to inadequate analgesia as the patient balances opioid intake with constipation symptoms.

Increased fluid and fibre intake, plus osmotic and stimulant laxatives, may provide sufficient prophylaxis, when started alongside the first opioid dose. (31) Opioid antagonists modified to prevent entry into the CNS (eg methylnaltrexone, naloxegol) are second-line remedies. Other drugs, such as lubiprostone, that increase fluid secretion into the GI tract, or those which increase gastric motility by non-opioid receptor mechanisms, are also available. (31)

Tolerance, dependence or addiction?

Fear of addiction can make patients reluctant to take opioids. It is important to distinguish between tolerance, physical dependence and true addiction.

Tolerance

Tolerance to opioids, where an increasing dose is required to achieve the same analgesic (or euphoric) effect, can occur within a few days or even a few hours of starting use. Tolerance to many of the adverse effects may also occur, but this happens more slowly than tolerance to the desired effect. This means an habitual user of opioids can take doses many times greater than the normal analgesic dose without experiencing dangerous 0IRD. (8,33)

Tolerance occurs when the entire pain pathway becomes desensitised to opioid actions, but specific mechanisms are not known. Receptor desensitisation and down-regulation--where exposure to a drug causes the number of its receptors to be reduced--may be factors. Adding to the confusion is the now-recognised phenomenon of opioid-induced hyperalgesia (OIH), where opioid drugs actually cause increased sensitivity to pain. (33)

With OIH, increasing pain may have the same origin as the underlying pain, or it could be from a different region and triggered by even mild stimulation. Pain increases if the dose of opioid is increased (unlike with tolerance, where increasing the dose should reduce the pain). The mechanisms underlying OIH are not known, but may involve reflexive up-regulation of systems that enhance pain. (33)
Box 1. Opioids for dyspnoea in
end-stage respiratory disease

OPIOIDS HAVE long been used to reduce respiratory
distress for patients with end-stage respiratory
disease, but the mechanisms involved are
complex. Regions of the brain involved in the
emotional aspects of pain are also responsible
for conscious control of breathing and triggering
the sensation of breathlessness. Activation of mu
receptors here may decrease the sensory feedback
that triggers the urge to breath in dyspnoea. (24)

Opioids may also act in end-stage disease by: (37)

* Reducing the brainstem respiratory centres'
responsiveness to high C02 and low oxygen that
may drive dyspnoea.

* Decreasing anxiety

* Decreasing oxygen demand due to sedation.


Physical dependence

Physical dependence is demonstrated by the appearance of abstinence syndrome when opioid therapy is abruptly stopped. Signs and symptoms of this syndrome include restlessness and anxiety, runny nose, abdominal pain and diarrhoea, shivering and piloerection, and tachycardia. (8) Physical dependence can occur following a relatively short period of opioid treatment. The mechanism is pharmacological and similar to the development of tolerance and resolves shortly after discontinuation of the drug. (34)

Addiction

Addiction is a neurobiological condition. Opioids increase the release of dopamine in the reward centres of the brain and induce long-term changes in their structure and function. Eight to 12 per cent of opioid users develop an addiction. (35) Addiction is characterised by: (34)

* Impaired control over use.

* Continued use, despite harm.

* Craving.

* Compulsive use.

It should be distinguished from pseudo-addiction, where poor pain control makes the patient focus on obtaining more of the analgesic. This behaviour goes away once pain relief is adequate.

Rising prescribing rates of opioids to treat chronic, non-cancer pain --with little reliable evidence of their effectiveness --has driven increasing rates of addiction throughout the developed world. (37) Use of opioids not only creates changes in reward pathways but, in chronic pain, also induces a learned association that triggers opioid use for even mild pain. (34) Abuse of prescription opioids has also driven an increase in heroin use.

CONCLUSION

Opioids remain the most effective form of treatment for moderate to severe acute and cancer pain. However, their use to manage chronic non-cancer pain is controversial. Use of opioid drugs has numerous adverse effects. An understanding of the mechanisms underlying both the analgesic and adverse effects helps health professionals provide the best care for patients needing strong pain relief.

* References for this article can be found at www.cpd4nurses.co.nz.

LEARNING OUTCOMES

After reading this article and completing the online learning activities, you should be able to:

* Describe the mechanisms of action of opioid drugs.

* Outline the underlying causes of key adverse events associated with opioid use.

* Discuss monitoring and detection of adverse events.

* Distinguish between tolerance, physical dependence and addiction. LEARNING OUTCOMES

After reading this article and completing the online learning activities, you should be able to:

* Describe the mechanisms of action of opioid drugs.

* Outline the underlying causes of key adverse events associated with opioid use.

* Discuss monitoring and detection of adverse events.

* Distinguish between tolerance, physical dependence and addiction.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.

CPD+nurses

Earn two hours of CPD

By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD).

Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.

These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.

Caption: Figure 1. Role of opioids in the nociceptor/pain pathway

Caption: Figure 2. Metabolism of morphine
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Title Annotation:CPD+nurses
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Report
Geographic Code:8NEWZ
Date:Sep 1, 2018
Words:3661
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