Chronic non-cancer pain: the appropriate use of opioids - Pathos

The gate control theory, formulated by Ronald Melzack and Patrick Wall in the 1960s, is one of the most influential models in the study of pain. Although its physiological details have been partly superseded—particularly due to the lack of evidence for a background nociceptive tone directly modulated by myelinated fibres—it remains a theory of extraordinary historical and conceptual importance. Its value lies in having introduced a radical shift in perspective: pain is no longer considered a simple linear transmission of impulses from peripheral receptors to the brain, but a dynamic phenomenon, modulated throughout the nervous system.

In this context, the mind plays an active role in modulating pain, being able to amplify it or, conversely, attenuate it.7 The powerful action of the inhibitory system is documented not only experimentally but also in the anthropological sphere: experiences of pain suppression observed in various cultures have been interpreted as manifestations of a complex central control, sometimes described as ‘magical’ due to its apparent incomprehensibility. From a neurochemical perspective, numerous mediators involved in peripheral and spinal nociceptive transmission are now known, including excitatory amino acids, substance P and bradykinin, as well as mediators of the descending inhibitory system such as endorphins, serotonin, noradrenaline, dopamine and GABA.4,13 However, the mechanisms regulating psychogenic pain or the affective component of pain are not yet fully understood.

It is now clear that pain cannot be reduced to a purely somatic phenomenon: it arises from the complex interaction between neurophysiological, cognitive and emotional components. In certain conditions, such as chronic pain, this integration can be profoundly altered, leading to states of amplification or dysfunction of the modulatory systems.6,7,9

In this sense, chronic pain can be interpreted as a condition of imbalance in the endogenous control systems, in which the regulation between facilitation and inhibition is compromised. This perspective has important clinical implications, suggesting that pain treatment cannot be limited to symptom suppression, but must consider the entire regulatory system, including neurophysiological, psychological and behavioural aspects.6-9

However, an understanding of the anatomical and functional pathways of pain is essential for interpreting the mechanisms through which nociceptive stimuli are transmitted, modulated and perceived. An analysis of the organisation of the nociceptive system, from peripheral structures to cortical centres, enables us to identify the main points of regulation of the pain signal. The first part will therefore describe the pain pathways and their mechanisms of transmission and modulation; subsequently, based on this knowledge, the role of opioids will be addressed, highlighting their main sites of action and the mechanisms through which they exert their analgesic effect.

The nociceptive system comprises the set of structures and mechanisms responsible for the detection, transmission, integration and modulation of stimuli that are potentially harmful to the body. 10,15 It is not a linear system, but a complex and dynamic network in which peripheral, spinal and central processes interact continuously to determine the experience of pain.7,8,10,15

The nociceptive process originates in nociceptors, specialised sensory neurons consisting of free nerve endings distributed throughout the skin, muscle and visceral tissues. These receptors are activated by potentially harmful mechanical, thermal or chemical stimuli. Tissue damage induces the release of inflammatory mediators, including prostaglandins, bradykinin and arachidonic acid derivatives, which sensitise the nociceptors and lower their activation threshold. In pathological conditions, silent nociceptors—which are normally unresponsive—are also recruited, contributing to peripheral sensitisation and the onset of hyperalgesia and allodynia.

Following depolarisation, the membrane undergoes a process of repolarisation mediated by the opening of potassium channels and the activity of the sodium-potassium pump, which restores the ionic gradient. The frequency of action potentials encodes the intensity of the stimulus, whilst the quality of pain depends on the type of receptor activated and the characteristics of the fibres involved. Myelinated Aδ fibres transmit rapid, acute and well-localised pain, whilst unmyelinated C fibres are responsible for slow, diffuse and persistent pain.10,15

The cell bodies of nociceptive neurons are located in the dorsal root ganglia, whilst their central projections reach the posterior horn of the spinal cord, where the first synapse with second-order neurons occurs.4 Synaptic transmission is mediated by the release of excitatory neurotransmitters, such as glutamate and substance P, which induce the depolarisation of postsynaptic neurons.15,16,17 However, this transmission is not passive; it is modulated by spinal interneurons and descending systems, which can either reduce or amplify the nociceptive signal, constituting an important control point, as also described by the gate control theory.9

After the spinal synapse, second-order neurons cross over and ascend in the anterolateral column of the spinal cord, forming the spinothalamic system. This comprises a neospinothalamic pathway, which rapidly transmits information to the thalamus, allowing the stimulus to be discriminated in terms of location and intensity, and a paleospinothalamic pathway, characterised by slower, more diffuse transmission and connections with the brainstem and the limbic system, which is responsible for the affective-emotional component of pain.4,7,15

The thalamus represents the main station for the integration of nociceptive information and acts as an interface between the ascending system and the cerebral cortex.

Thalamic projections reach the primary and secondary somatosensory cortex, located in Brodmann areas 3, 1 and 2, which are responsible for stimulus discrimination, as well as other cortical regions, including the insula, the anterior cingulate cortex and the prefrontal cortex, which are involved respectively in body awareness, the affective component and the cognitive processes of pain. The reciprocal connections between the thalamus and the cortex, particularly with the frontal cortex, allow for modulatory control of the pain experience, integrating sensory, emotional and cognitive aspects.4,7,15

In parallel with the ascending pathways, the nociceptive system is regulated by descending pathways originating from cortical and subcortical structures, including the prefrontal cortex, the limbic system, the periaqueductal grey, the raphe nuclei and the locus coeruleus.4,15 These systems modulate nociceptive transmission at the spinal level through presynaptic and postsynaptic inhibitory mechanisms, mediated by substances such as endogenous opioids, serotonin, noradrenaline and GABA. Activation of opioid receptors, particularly μ and κ, leads to a reduction in the release of excitatory neurotransmitters and a decrease in neuronal excitability, contributing to the analgesic effect.2,4,18

Overall, pain arises from the interaction between peripheral transduction mechanisms, spinal integration processes, ascending pathways, thalamocortical integration and descending modulation systems. It is therefore not a passive signal, but a dynamic and regulated process, in which the balance between excitatory and inhibitory systems determines the intensity and meaning of the pain experience.7,15 Understanding these mechanisms is a fundamental prerequisite for the clinical approach to pain and for the appropriate use of therapeutic strategies, particularly opioids, which act precisely on the systems that modulate nociceptive transmission.2,4,7,8

The transmission of nociceptive stimuli is not a linear, passive process, but rather the result of continuous integration and modulation throughout the central nervous system. Following peripheral transduction and spinal transmission, nociceptive information is in fact profoundly modulated by descending control systems of cortical and subcortical origin, which can either amplify or reduce its perception.7,12

Cortical control of pain is achieved through complex circuits involving the prefrontal cortex, the insula, the anterior cingulate cortex and subcortical structures such as the thalamus, the hypothalamus and the periaqueductal grey. These regions give rise to descending pathways that reach the brainstem and spinal cord, where they modulate the activity of nociceptive neurons in the dorsal horn.4,15 This descending inhibitory system is mediated by numerous neurotransmitters and neuromodulators, including endorphins, serotonin, noradrenaline, dopamine and GABA, which act by reducing the transmission of the nociceptive stimulus or by raising the threshold for neuronal activation.4,13

The thalamus is a pivotal structure in the integration of nociceptive information, functioning as a sorting hub between the ascending pathways and the various cortical areas.15 The neospinothalamic pathways project primarily to the posterior ventral nuclei of the thalamus, which in turn transmit the information to the primary and secondary somatosensory cortex. This enables the discrimination of the stimulus in terms of location, intensity and quality. Concurrently, the paleospinothalamic pathways extend to medial and intralaminar thalamic nuclei, which project to limbic and associative cortical structures, thereby contributing to the emotional-affective dimension of pain.7,15

Opioids that are frequently employed in the management of moderate pain include codeine, tramadol and tapentadol. These medications are distinguished by a mechanism of action that exhibits certain similarities, yet they also possess notable pharmacokinetic and pharmacodynamic distinctions.8,13,18
Codeine is a widely utilised pharmaceutical agent for the management of moderate pain. It is commercially available in various formulations, primarily in combination with paracetamol, including tablets, effervescent tablets and granules. The substance under discussion is chiefly a prodrug, the analgesic activity of which depends on its conversion in the liver to morphine, a process that is mediated by cytochrome CYP2D6. This results in considerable inter-individual variability in response: in individuals with reduced enzymatic activity (slow metabolisers), the analgesic effect is poor or absent, whilst in rapid metabolisers it may be more intense but of shorter duration and associated with a greater risk of adverse effects. Codeine also possesses modest direct agonist activity on μ-receptors, but its primary antinociceptive effect is linked to its conversion to morphine.

Tramadol is a synthetic opioid that is available in a variety of formulations, including drops, immediate-release and prolonged-release tablets, suppositories and ampoules. It is frequently combined with paracetamol or ketoprofen. The mechanism of action of the substance under investigation is twofold. Firstly, it acts as a μ-receptor agonist; secondly, it inhibits the reuptake of serotonin and noradrenaline. This dual action contributes to the modulation of descending pain pathways. Tramadol is also partly a prodrug, activated by CYP2D6. Its efficacy may be significantly reduced in the presence of inhibitors of this enzyme or in individuals with a genetic deficiency in its activity. Furthermore, due to its serotonergic component, it may interact with other serotonergic drugs, increasing the risk of serotonin syndrome and, in some cases, epileptic seizures.

Tapentadol signifies a pharmacological evolution of tramadol, characterised by a more direct dual mechanism of action, namely μ-receptor agonism and inhibition of noradrenaline reuptake, without significant serotonergic activity. This characteristic has been demonstrated to reduce the risk of serotonergic interactions, whilst maintaining effective analgesic action. The medication is available in the form of prolonged-release tablets, which are typically prescribed for twice-daily administration. Absorption of the drug is rapid, and it is primarily metabolised via hepatic conjugation, with elimination occurring predominantly via the kidneys. However, it is important to note that tapentadol has the potential to elevate noradrenaline levels. Consequently, its use in conjunction with monoamine oxidase inhibitors or other noradrenergic-active medications necessitates caution, as there exists a heightened risk of tachycardia and hypertensive crises.18

While these opioids possess reduced analgesic efficacy in comparison to strong opioids, they are frequently employed in the management of moderate pain or as an intermediate step in the therapeutic ladder. It is imperative to consider individual variability in response and potential drug interactions when utilising these medications.5,8

Strong opioids represent the cornerstone of severe pain management and include compounds with high analgesic efficacy, but also with a heterogeneous pharmacokinetic and pharmacodynamic profile, which influences their clinical use. The most prominent opioids in this category include morphine, oxycodone, hydromorphone, fentanyl, buprenorphine and methadone.8,18
Morphine is widely regarded as the gold standard by which the efficacy of other opioids can be gauged.8,18 The medication is available in various formulations, both immediate-release and prolonged-release, which allow for flexible dose titration. The predominant metabolic process in this instance is hepatic glucuronidation, which results in the formation of active metabolites that are subsequently excreted by the kidneys. Oxycodone is a semi-synthetic opioid that exhibits a higher degree of potency in comparison to morphine and demonstrates satisfactory oral bioavailability. Its metabolic processes are predominantly facilitated by the cytochrome P450 system (CYP2D6 and CYP3A4), which renders it susceptible to inter-individual variability and the occurrence of drug interactions. Hydromorphone, a more potent analgesic than morphine, exhibits more predictable pharmacokinetics due to its primary glucuronidation rather than cytochrome P450-mediated metabolism. This characteristic renders it particularly advantageous for patients with a high risk of drug interactions or renal impairment.

Fentanyl is a highly lipophilic opioid, available principally in transdermal or transmucosal formulations. The transdermal route enables the sustained release of the drug over a period of approximately 72 hours, thereby ensuring the maintenance of stable control of chronic pain. In contrast, transmucosal formulations are indicated for the treatment of severe episodic pain, particularly within the field of oncology. The primary metabolic pathway is via CYP3A4, which renders the subject susceptible to drug interactions that may result in increased plasma levels and an elevated risk of respiratory depression.

Buprenorphine is a semi-synthetic opioid with a distinctive receptor profile. It acts as a partial agonist at μ-receptors and an antagonist at κ-receptors. In contrast to pure agonists, such as morphine and oxycodone, which activate both receptors, buprenorphine exerts an inhibitory effect on the κ-receptors. These receptors have been implicated in the induction of dysphoric and psychotomimetic effects, as well as certain components of the stress response.20-22 This antagonism contributes to an enhanced tolerability profile, thereby reducing adverse effects on mood and potentially attenuating central sensitisation and hyperalgesia. The substance exhibits a high degree of affinity for μ receptors, in addition to partial agonist activity. This combination results in the observation of favourable analgesic efficacy, accompanied by a reduced risk of severe respiratory depression when compared to full agonists.

Moreover, the pharmaceutical compound is available in a transdermal formulation, offering sustained drug release and good clinical manageability. It is primarily metabolised by the liver and excreted via the bile, making it relatively safe for patients with renal impairment.

Methadone is a synthetic opioid characterised by high analgesic efficacy and a long, variable half-life, which renders its clinical use complex. In opioid rotation and the management of neuropathic pain may be useful in selected case of neuropathic pain; it necessitates expertise and meticulous observation due to the potential for accumulation and overdose. The cytochrome P450 system is the principal mediator of metabolism, with the potential for significant drug interactions. A significant concern is the risk of QT interval prolongation and ventricular arrhythmias, which necessitates caution in the prescription of medication and electrocardiographic monitoring in patients considered to be at risk.

The selection of an appropriate opioid medication is a decision that must be made on an individual basis, taking into account the patient's characteristics, the nature of the pain, comorbidities, and potential drug interactions. The knowledge of the specific properties of each drug allows for the optimisation of analgesic efficacy whilst minimising adverse effects. This can be achieved through strategies such as opioid rotation and dose adjustment.5,7,8

Opioids have been demonstrated to be associated with a range of adverse effects, including sedation, nausea, vomiting, cognitive impairment and, most notably, constipation, which is the most prevalent and persistent adverse effect. A considerable proportion of patients report adverse events, which can lead to poor adherence or discontinuation of treatment, particularly in the early stages of therapy. It has been reported that, in the long term, endocrine changes, reduced bone density and an increased risk of fractures have also been observed. In addition, possible effects on the immune system have been postulated.8

From a pharmacological perspective, opioid therapy is associated with the development of tolerance and physical dependence. A key aspect of this phenomenon is what is termed 'selective tolerance', whereby certain adverse effects, such as nausea, sedation and euphoria, tend to diminish over time, whilst others, such as constipation, persist. This phenomenon is of significant clinical importance and forms the basis of titration strategies.

Nevertheless, the primary concern regarding the utilisation of opioids pertains to the potential for abuse and the development of psychological dependence. International experience, in particular the so-called 'opioid crisis' observed in North America,5 has highlighted the consequences of the widespread and inadequately controlled use of these drugs, with a marked increase in opioid-related mortality in the United States and Canada. This phenomenon has prompted a comprehensive review of prescribing practices, resulting in the introduction of more restrictive strategies, dosage limits and stricter monitoring systems.

In contrast, in European countries, despite a gradual increase in opioid use since the 1990s, consumption remains generally lower than in North America and the problem of abuse appears more contained. In Italy, the implementation of Law 38/2010 has contributed to the enhancement of access to pain management and palliative care, resulting in an increase in prescriptions, while consumption levels persist at a lower rate compared to other Western countries. These discrepancies underscore the necessity for a balanced approach that encompasses both the facilitation of treatment and the management of risk.

In patients who have not yet developed a tolerance to opioids, the absence of tolerance renders them particularly susceptible to adverse effects. Consequently, the fundamental strategy to enhance tolerability and promote therapeutic adherence is to initiate low doses and to progress gradually.5,8 The utilisation of immediate-release formulations enables the initiation of treatment with minimal doses, followed by gradual adjustment to ensure the safety and efficacy of the treatment. This approach mitigates the risk of adverse events. However, in specific clinical conditions, such as difficulties in managing the therapeutic regimen, dysphagia, or the need to use transdermal formulations, it may be appropriate to resort to extended-release formulations. In view of these elements, the initiation of opioid therapy necessitates an initial comprehensive and multidimensional assessment.5-9

A comprehensive medical history must be obtained, encompassing the nature of the pain, prior treatments, ongoing therapies, functional status, sleep quality, and psychological aspects, including any history of substance abuse or dependence. This evaluation facilitates a more precise definition of treatment indications and the identification of potential risk factors. The therapeutic planning process must be communicated to the patient, with the objective of not only managing pain but also facilitating the recovery of function and enhancing the patient's quality of life. It is imperative to establish clear and quantifiable goals that facilitate the evaluation of treatment effectiveness over time and inform any necessary therapeutic modifications. Furthermore, the plan must include strategies for the gradual reduction or discontinuation of opioids if the benefits are deemed to be inadequate.

During the titration phase, patients must be adequately informed about the risks of sedation and encouraged to avoid hazardous activities until a stable dosage is achieved. It is imperative that they are cognisant of the risks associated with combining opioids with alcohol, benzodiazepines, or other sedative drugs, which can increase the risk of respiratory depression. The long-term management of opioid therapy necessitates continuous monitoring and a flexible approach. In cases where it is deemed appropriate, deprescription represents a multifaceted process that necessitates meticulous planning and comprehensive support. In circumstances where adverse effects are unmanageable, there is an inability to discontinue treatment, or the patient is highly complex, it is advisable to consult with specialists in pain medicine. For patients who are more vulnerable, a multidisciplinary approach should be adopted.

In the context of chronic non-cancer pain, the utilisation of opioids should be approached with a degree of caution, employing a structured and personalised strategy. This strategy should be informed by international experiences and be designed to optimise both the analgesic and functional benefits of the therapy, while concomitantly minimising the associated risks.