Opioids

Opium is the product of condensation of the lactiferous juice coming from the capsules of Papaver somniferum (Figures 1a and 1b). Opiates are substances whose chemical analgesic properties have been known for a long time. The first undisputed reference to opium has been found in the writings of Theophrastus (Fig. 2) in the third century BC, in which the author named opium meconion (µὴκωνίὸν), as it turned black when exposed to air taking on the appearance of the intestinal contents of newborns. Scribonio Largo, in AD40, described the method used to extract opium, pointing out thatit was extracted from poppy capsules and not from the leaves. Arab doctors were also well aware of the possible medical uses of opium and, thanks to travellers, the substance was spread throughout the Western and Eastern world to be used mainly for the control of dysentery.

Opium contains more than 20 alkaloid compounds. The first alkaloid that was isolated by Sertürner in 1806 was named morphine after Morpheus, the Greek god of sleep; the other alkaloids were extracted soon thereafter. Since the mid-nineteenth century, the entire medical world began to use single alkaloids instead of the old pure opium-based preparations.

Derivativesand analogues of opium were synthesised with the purpose of trying to reduce the side effects (nausea, vomiting, constipation, respiratory depression, death). Unfortunately, this meant that, at least in the early attempts, safer, but less effective drugs than the classical opioids were introduced in clinical use. Subsequently, research allowed to synthesise opioid antagonists, and even compounds with a mixed activity, meaning with both agonist and antagonist properties. This amplified very much the flexibility of therapeutic use and such substances contributed to the development of an important knowledge on the mechanism of action of these molecules.

The large-scale production of morphine for medical use started in 1827, by Merck & Co., while the first parenteral administration of the drug was performed in 1853 by the Scotsman Alexander Wood (Fig. 3) (co-inventor of the hypodermic syringe simultaneously with Pravatz), who inoculated morphine subcutaneously in patients affected by chronic neuralgias.

OPIOID RECEPTORS

Until the early1970s, the mechanism of action of morphine, heroin and of other opioid agents, although well described, had always been studied in relation to their interaction with other neurotransmitter systems, such as monoaminergic and cholinergic systems.

Someresearchers hypothesised the existence of a specific receptor for these substances, due to the structural equivalence of opiate ligands, but they could not prove itspresence in the brain.It was only in 1973 that researchers from three different laboratories were able to identify, through the use of radio-ligands, the encephalic sites where the opioid receptors were concentrated. Based on some studies carried out on spinalised dogs, Martin and colleagues documented, in 1976, the existence of three distinct types of receptors able to interact with exogenous or endogenous opioids (μ, κ, σ); one year later, Lord and colleagues identified a fourth type of receptor, which was called δ, which seems to be the main target of endogenous opioids. In 1994 another member of the family of opioid receptors was also cloned, named nociceptin/orphanin FQ (N/OFQ), which has a significant structural homology over an extended sequence with the other receptors of its family, but which did not show any interaction with any class of opioid ligands, except for nociceptin, which, on the contrary, shows poor affinity towards all the other receptors.

From the early1980shighly selective ligands for different types of receptors have become available, and this has made ​​possible the definition of the characteristics of the binding sites of each of them and the determination of their anatomical location through the use of autoradiographic techniques. Each receptor has, in fact, a characteristic distribution in the brain, spinal cord and peripheral organs (Mansour et al., 1988; Neal et al., 1999), corresponding with specific functions and characteristics:

• δ receptors, of which at least 2 subtypes exist,predominantly interact with peptides produced by the organism (met-enkephalin, leu-enkephalin, dynorphin and endorphins) and consequently are not clinically relevant;
• κ receptors probably induce analgesia and sedation by acting on the spinal cord; they do not cause respiratory depression, but they can cause dysphoria;
• σ receptors seem to mediate many of the side effects of opioids; they seem responsible for maniacal symptoms and for other psychotic-like effects as well as for some vasomotor effects; these receptors are particularly concentrated in the hippocampus and their stimulation causes, in dogs, mydriasis, tachypnea, tachycardia and delirium and triggers a withdrawal syndrome in morphine-dependent animals. It was previously suggested that they were also responsible for analgesia but, currently, they do not seem to be involved in controlling pain and their classification remains uncertain.
• μ receptors, of which three subtypes are recognised: μ1 receptors have high affinity for opioids and are able to produce supraspinal analgesia as they are  localised mainly at the level of the periaqueductal grey matter; once they are stimulated they trigger the descending inhibitory pathways which modulate the transmission of painful stimuli in the dorsal horns of the spinal cord. µ2 receptors are less akin to exogenous opioids compared to the first subtype, they are present in the spinal cord and they are responsible for the characteristic respiratory depression induced by these molecules. µ3 receptors have a predominant immunomodulatory action as they are present in the leucocyte membrane (Corletto, 2004). Some of the consequences generated by the activation of this group of receptors includemuscle rigidity, cough inhibition, orthostatic hypotension, decreased gastrointestinal motility and increased secretion of ADH. Eventually, together with δ-type receptors, they are responsible for the occurrence of nausea, vomiting and miosis (Gustein, 2006).

A new classification is currently gaining ground, based on the cloning of receptor types, which distinguishes them in: OP1 (δ), OP2 (κ), OP3 (µ) and ORL1 (receptor N/OFQ) (Lascelles, 2000).

For a complete understanding of opioids it is extremely important to place the receptors in their anatomical and physiological context. The type of pain controlled by opioids must in fact be considered within the context of the brain circuits which modulate analgesia and the functions of the various types of receptors within such circuits (Fields, 1991).

It is well documentedthat the analgesic effects of opioids derive from their capability to directly inhibit the ascending transmission of nociceptive information at the level of the dorsal horns of the spinal cord and to activate the circuits for the control of pain descending from the midbrain, through the rostral ventro-medial spinal cord and down to the dorsal horns. Opioid peptides and their receptors have been identified within these descending circuits of pain control (Mansour e tal., 1995; Gustein et al., 1998). The evaluation of discrepancies among the levels of ligands and the expression of mRNA, which translates information for them, has allowed to establish that the majority of the μ receptor sites are located at pre-synaptic level on the terminations of primary afferent nociceptive nerves. A similar discrepancy among μ receptors and the expression of mRNA was observed in the dorsolateral PAG (Gutstein et al., 1998).

The mRNA for the δ receptors and its receptor sites have been highlighted in the ventral and ventrolateral quadrants of the PAG, of the pontine reticular formation and of the giant-cell reticular nuclei, but only low levels are present in the median raphe and in the nucleus raphe magnus. Just like for the μ receptors, there are numerous δ receptor sites in the dorsal horns, but there is no detectable expression of mRNA; this suggests an important role in the pre-synaptic action of δ receptors with regard to spinal analgesia. A similar situation has also been observed for κreceptors.

Although mRNA was observed in the dorsal root ganglia for all the three types of receptors, the receptors are localised in different types of primary afferent cells: the mRNA for the μ-type receptors is present in medium and large diameter cells, that for δ-type receptors in large diameter cells and that for κ-type receptors in small and medium size cells (Mansour et al., 1995). This different localisation can be associated with functional differences which determine the way they act in the modulation of pain.

The distribution ofopioid receptors in the descending circuits for the control of pain indicates a substantial overlap among μ and κ type receptors. These are anatomically different from the δ-type in the periaqueductal grey matter, in the median raphe and in the nucleus raphe magnus (Gustein etal., 1998). A similar differentiation is also evident in the thalamus, suggesting that the interaction among  μ and κ receptors can be important for the modulation of nociceptive transmission in the higher encephalic centres, as in the dorsal horns of the spinal cord.

MECHANISM OF ACTION 

The mechanism of actionresults in a pre- and postsynaptic inhibitory modulation in the CNS, in the spinal cord by inhibiting the transmission of the impulse at the level of projection neurons, and in the midbrain and medulla oblongata, by stimulating the release of noradrenaline and serotonin. In fact, at presynaptic level (A-δ and C fibres) opioids inhibit the release of substance P and glutamate, excitatory mediators involved in the transmission of nociceptive impulses in the spinal cord.At postsynaptic level, however, opioids may change the neuronal ionic currents (calcium and potassium channels) through their inhibition or modulation, resulting in hyperpolarisation of the membranes and in decreased frequency and amplitude of action potentials of cells of laminae I, II and V of the dorsal horns. In particular, the stimulation of the δ and μ type receptors involves a conformational change of the same receptors and the activation of a guanosine nucleotide effector (G effector) (Fig. 4). The activation ofthe G effector  induces, in turn, the inhibition of adenylate cyclase, which causes a reduction in the synthesis of cyclic AMP, increased potassium conductance and neuronal hyperpolarisation, resulting in a reduced discharge capacity. Instead, the bond to κ type receptors activates an effector which determines reduction in the flow of calciumions which is essential for the release of substance P. The σ-type receptor reduces the transmission to supraspinal centres through the inhibition of the release of N-methyl-D-aspartate (NMDA).

The pharmacological action of the individual drugs will depend on the opioid receptors they interact with, on the selectivity of such bond, on the normally associated physiological effects, on the activation of each receptor and on their localisation in the body (in fact, the interaction with supraspinal m receptors would seem to result in better analgesia compared to that obtained by binding to spinal μ receptors), as well as on the type of bond between receptor and opioid.

CLASSIFICATION OF OPIOIDS

The variousopioid drugs show different affinity and selectivity for different receptors and, therefore, they have different chemical behaviours one with the other; for this reason they have been divided into three classes:

1.  Pure agonists (morphine, meperidine, oxymorphone, codeine, methadone, fentanyl, alfentanil, sufentanil, remifentanil);

2.     Agonist-antagonists (butorphanol, pentazocine, nalbuphine);

3.     Partial agonists (buprenorphine);

4.     Antagonists (naloxone, naltrexone, nalmefene).

The first class of opioids includes the molecules which show high affinity for μ-type receptors, but which can also bind to κ and δ receptors. These molecules can produce excellent analgesia, even in the presence of severe pain, and a certain degree of sedation. In addition, pure agonistsallow a good control of pain because they have a linear dose-effect ratio and they do not present the so-called ceiling effect, contrary to what happens for partial agonists and agonist-antagonists. This phenomenon implies that, by increasing the doses of the drug beyond a certain threshold, the analgesic effect is antagonised, causing a reduction in the level of analgesia (Fernandez, 2001). The drugs belonging to the second class of opioids (agonist-antagonists) behave as agonists towards some receptors (κ and probably δ-type) and as antagonists towards some others (µ). The third class of opioids (partial agonists), manifest only a partial agonist activity towards μ receptors for which they show, however, a high affinity. These opioids (second and third class) have the ability to partially antagonise the action of pure agonists; this action may be useful when there is the need to eliminate some side effects such as respiratory depression or dysphoria induced by pure agonists. As regards partial agonists, although they activate μ receptors only partially, they bind to them very strongly, and are thus hardly antagonisable by both pure agonists and antagonists. Finally, as far as opioid antagonists are concerned, they bind to the receptor without activating signal transduction pathways and therefore they do not cause any analgesic effect. Their antagonist action is mainly addressed to μ-type receptors and, to a minor extent, towards δ and κ-type receptors. They are able to antagonise all the pharmacological effects of the other opioids and this obviously includes the cancellation of analgesia. They are used in the course of severe cardio-respiratory depression caused by the incorrect administration of opioid agonists.

PHARMACOKINETICS AND PHARMACODYNAMICS

The absorption of opioids after intramuscular, subcutaneous and parenteral administration is usually regular and efficient. Nevertheless, the oral administration cannot be used much, due to a hepatic first pass metabolism effect which  considerably reduces the bioavailability of opioids; for example, the oral absorption of morphine is of approximately 25% (Gustein, 2006). For this reason, human patients are not recommended to swallow solutions or pills of opioids for oral use (morphine, fentanyl), but to keep them instead in the mouth in contact with the mucosa in order to facilitate a slow mucosal absorption; this is either not easy or impossible in our veterinary patients.

On the contrary, absorption by the rectal mucosa is effective and some drugs, such as morphine, are available as suppositories, but the use of this route of administration in animals is not yet well studied. More lipophilic opioids are rapidly absorbed through the nasal and buccal mucosa (Weinberg et al.,1988) and, if lipophilicity is particularly strong, as in the case of fentanyl or buprenorphine, they are also absorbed via the transdermal route (Portenoy et al., 1993), by using  appropriate patches which slowly release the active principle which can reach the bloodstream after crossing the cutis.

Opioids can adequately penetrate into the spinal cord after intrathecal or epidural administration, but the effects are different especially depending on the lipophilicity of the drug. In fact, highly fat-soluble molecules will give a more segmental analgesia than water-soluble molecules (morphine), with very localised effects due to the rapid absorption in the neural tissue, but with a lower duration of action because of the redistribution into the systemic circulation (Bufalari, 2008).

When opioids are administered intravenously their action is very fast (for example, in humans, sufentanil shows its maximum effect after approximately 7 minutes); morphine, instead, has a slower onset of action, due to the difference in the fractions of uptake and entry into the CNS. When compared to fat-soluble opioids such as codeine, heroin and methadone,  morphine is indeed considerably slower in crossing the blood-brain barrier.

The majority ofopioids are metabolised in the liver through the conjunction with glucuronic acid or through the abolition of methylic groups from the original molecule. The hepatic metabolites are excreted via the kidneys. The elimination with the bile and the enterohepatic circulation may prolong the pharmacological effects of opioids, as well as the formation of active metabolites (Boothe, 2001).

EFFECTS OF THE MOST USED OPIOIDS IN CLINICAL PROCEDURES

Analgesia and sedation
Generally, the degree of analgesia, its duration and, therefore, the effectiveness of the drug in controlling mild, moderate or severe pain, will depend on the opioid class and on the administered dose (Nolan, 2000). The different analgesic power of the various compounds is assessed using morphine as a model, which has been assigned, by convention, the value of 1 (Table 1).

Table 1. Analgesic power of some opioids.

In addition to analgesia opioids induce a certain sedative effect, which is more pronounced in the dog than in the cat (Fernandez, 2001). However, even in this case, its onset varies according to the active principle chosen and it is linked to the interaction of the drug with the m-type receptors and, to a lesser extent, with the k-type receptors. Sedation may be an advantage or a disadvantage depending on the patient's clinical condition (Boothe, 2001).As a secondary effect,hyperexcitation or euphoria can occur, especially if high doses are used in conscious animals.Euphoria, in both the dog and cat, is more frequent in healthy patients or, in any case, in patients which show no pain, and its incidence can be diminished by the combined use of tranquilisers (Fernandez, 2001).

In humans, opioids cause analgesia, drowsiness,mood alterations and blunting of the sensorium up to loss of consciousness (Gutstein and Akil, 2006).

Respiratory depression
Opioids cause a decreased activity of the bulbar respiratory centres, which therefore present an inferior sensitivity to CO2 and to hypoxia (Alvarez, 2005). A decrease in the respiratory minute volume is also present, caused by a decrease in the respiratory rate, rather than in the amplitude, all the way to a state of apnoea, due to the depression of the pontine and bulbar centres. This effect is dose-dependent and seems to be related to the activation of μ receptors; it actually occurs especially after the administration of pure opioid agonists. Respiratory depression can lead to CO2 accumulation, which, in turn, produces encephalic vasodilatation, thereby increasing the cerebral blood flow and the cerebrospinal fluid pressure. When treating patients which have suffered from head trauma or which have to undergo CNS surgical procedures special attention must be paid to the control of ventilation (maintaining a state of normocapnia).

Panting (Video 1) or shallow and frequent breaths accompanied by sialorrhea are commonly present, episodes not so much caused by an effect on the respiratory centres, but rather by the interaction with the hypothalamic thermoregulatory centre; this phenomenon is generally temporary and the remission is spontaneous.

Effects on the CNS
Opioids attenuate the cough reflex, by exerting a direct effect on the cough bulbar centre; the suppression of this reflex is mediated by the opiate receptors located in the medulla oblongata. The mechanism is not well known, but the antitussive action is not correlated to either analgesia or respiratory depression. Codeine reduces coughing at doses lower than those needed to induce analgesia (Alvarez, 2005). An important aspect is that this action could increase the subject’s tolerance to the tracheal tube and delay the extubation phase (Papich, 2000).

Morphine-like molecules can inducenausea and vomiting via a direct stimulation of the chemoreceptor trigger zone (CTZ) located in the area postrema of the medulla oblongata. Furthermore, morphine increases the sensitivity of vestibular centres (Gustein, 2006). The emetic effect of pure agonists varies widely depending on the animal species: chickens and pigs are refractory to the majority of central emetic drugs, unlike what occurs in the dog and cat; the cat, however, requires considerably higher doses of morphine or apomorphine for the induction of vomiting compared to the dog. Finally, in this species, vomiting is usually preceded by sialorrhea, nausea and often also by defecation (Boothe, 2001).

In the dog and in humans, opioids induce miosis in response to the stimulation of μ and k receptors located at the level of the Edinger-Westphal nucleus of the oculomotor nerve, while in the cat and the horse the effect is mydriatic; this depends on the fact that, although at the level of the iris morphyne activates the parasympathetic tone (increasing the frequency of spontaneous discharge of the potentials from the photosensitive neurons to the anterior oculomotor nucleus), the miotic effect is cancelled by an increased release of catecholamines from the adrenal glands, which causes mydriasis (Boothe, 2001). Finally, in all cases, in the presence of severe hypoxia miosis converts into mydriasis.

Opioids alter the equilibrium of the hypothalamic thermoregulatory centre and determine, in the dog and cat, either a slight decrease in body temperature or an increase (panting) (Branson, 1996). 

The administration of morphine also alters the release of hormones and, as a consequence, plasma concentrations of testosterone and cortisol will become lower. The increased secretion of antidiuretic hormone may be the cause, in dogs, of decreased urination, by even 90%; moreover, morphine increases the tone of the bladder detrusor muscle, making urination even more difficult.

Cardiocirculatory effects
At cardiovascular level the effects of opioids are limited to only bradycardia, thus making them relatively safe drugs in the majority of patients. Pure opioid agonists may act on the vasomotor centre, resulting in moderate and transient arterial and venous vasodilatation with consequent reduction in the pre- and post-load and in hypotension. In order to mitigate these effects it is preferable to administer opioids by very slow intravenous injection (2-3 minutes). Some morphine-like agents (e.g. meperidine) can induce the release of histamine and, for these opioids, the intravenous route should possibly be avoided.

Bradycardia occurs frequently with the administration of many opioids and is caused by the stimulation of the vagus nerve; pethidine is able to induce a moderate tachycardia, thanks to its antimuscarinic action (Alvarez, 2005; Rang, 2004) (Video 2). Parasympathomimetic effects are, however, easily managed through the use of atropine and glycopyrrolate (Fernandez, 2001; Papich, 2000). Fentanyl and derivatives are less hypotensive, they ensure a better cardiovascular stability and do not stimulate the release of histamine from mast cells. High doses of fentanyl or sufentanil are commonly used in the premedication of patients which have to undergo cardiovascular surgery or which suffer from heart failure (Gustein et al., 2006).

Gastrointestinal effects
Opioid agonists increase the muscle tone in the gastrointestinal tract and inhibit the neurogenic activity resulting in a reduced motility. As a result, delayed gastric emptying, reduced intestinal peristalsis and sphincter contraction are present. The clinical manifestations are constipation and decreased pancreatic and bile secretion, due to an increased pressure in the biliary tract caused by hypertonicity of the sphincter of Oddi. This phenomenon has a central and a peripheral component and it involves, basically, μ receptors, making it possible to use opioids as anti-diarrhoeal drugs (their primary use in human medicine was, in fact, related to this therapeutic action).

Histamine release
Meperidine, morphine and buprenorphine trigger the release of histamine in vitro; in vivo meperidine is certainly the most dangerous substance from this point of view. Nalbuphine causes histamine release in humans, but not in the dog (Guedes, 2006). Butorphanol, fentanyl and its derivatives and oxymorphone do not induce this release either in humans or in dogs. The opioids which release histamine act directly on mast cells, inducing a partially calcium-dependent non-cytotoxic degranulation. For this type of degranulation, which however does not seem so severe after intramuscular injection, it is not yet clear if the bond to the opioid receptors and their activation are necessary. In any case, the degranulation is exacerbated in the event of rapid intravenous administration of high doses. However, since the degranulation depends on the dose and the route of administration used, the use of reduced doses administered continuously and slowly, in order to reduce drug concentration peaks in the plasma, should decrease the possibility of developing side effects caused by the release of histamine. The main adverse events are hypotension and tachycardia, however bronchoconstriction, cardiovascular collapse, pruritus and urticaria may also be present (Figures 5 and 6) (Shepherd, 2003).

Pharmacological tolerance and addiction
Inthe case of chronic treatment with opioids with time there is a decreased intensity in the response or a shorter duration of action, which forces a gradual dose increase. This is an effect common to all classes of opioids, regardless of the type of receptor being activated. The NMDA glutamate receptor seems to be involved in the development of tolerance towards the action of these molecules. A prolonged administration of opioids activates this receptor, thus decreasing its effectiveness. For this reason, the use of drugs which block the receptor (methadone has the property of binding to NMDA receptors) allows to reduce opioid tolerance and physical addiction, the latter being characterised by a withdrawal syndrome caused by the sudden cessation of the chronically administered opioid (Nolan, 2000).

Suggested readings

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