2. Opioids

The use of opioids has significantly increased during the last decade and concomitantly the occurrence of related ADRs has become more frequent [3, 17]. Opioids are, by definition, ligands for opioid neuroreceptors, thereby modulating them and their associated responses [3]. With opioid receptors controlling a variety of physiological processes, exogenous opioid application results, therefore, in an imbalance in receptor activity and a potential plethora of side effects.

covering specific pain relief needs, opioid medications and nonsteroidal anti-inflammatory

Pain relief management teams have to be aware of the exact nature of the pain itself and its intensity, and must be able to differentiate between acute and chronic pain. These are not only essential factors for pain management itself, but this could also lead to the consideration of possible adverse drug reactions (ADRs) from analgesic use. Indeed, when implementing pain relief management, one must consider the best practice to alleviate pain directly, along with the possibility of having ADRs which would then defeat the purpose of analgesics use itself [5–8]. Additionally, chronic pain is associated with an increased incidence of mental health issues such as anxiety and depression [9]; thus, there is a need to extend the consequences of

The proper use of analgesics, that is, targeted drug use against specific types of pain, can avoid or at least minimize ADRs. In this regard, scientific studies reporting on ADRs caused by analgesics become an invaluable tool to predict and prevent ADRs and to evaluate the safety of analgesics in different pain relief practices. While short-term side effects are generally easier to observe, long-term effects, particularly in chronic analgesic users, need specially designed studies or a careful review of previous literature. In the last few years, more literature has been made available that addresses ADRs of both the opioid and NSAID type, allowing for the re-evaluation of the safety of these two medication classes, including their

In order to draw attention to analgesic an their risks and to minimize the negative consequences related to their use, the present review comprises a synthesis of the most important safety issues described in scientific literature. This stands as a broad overview of the topic, providing a basic understanding of safety issues associated with analgesics and a starting

The ADRs associated with the two most commonly used analgesic classes, opioid and nonsteroidal anti-inflammatory drugs (NSAID), discussing their common adverse effects and how these can influence their usability in clinical applications. In recent years, more and more longterm studies have been published providing an insight into the potential risks of long-term analgesic use, this chapter provides a thorough overview. This is particularly important when discussing opioid analgesics, whose chronic use can lead to analgesic tolerance and even addiction. A full description of the potential problems derived from analgesic use represents

The use of opioids has significantly increased during the last decade and concomitantly the occurrence of related ADRs has become more frequent [3, 17]. Opioids are, by definition, ligands for opioid neuroreceptors, thereby modulating them and their associated responses [3]. With opioid receptors controlling a variety of physiological processes, exogenous opioid

the first step in optimizing protocols for its safe application in clinical settings.

drugs (NSAIDs) remain the most commonly used analgesics [1, 3, 4].

inefficient pain relief beyond pain management alone.

170 Pain Relief - From Analgesics to Alternative Therapies

point for further understanding of the subject at hand.

chronic long term use [10–16].

2. Opioids

Sedation is a common short-term ADR because of the anticholinergic effect of opioids. Drowsiness, sedation, nausea and vomiting could all be seen after treatment with opioids, and usually occurs in dosage transition states. Sedation represents the best early clinical indicator of respiratory depression [18]. A number of blind studies confirm this effect which seems particularly evident for methylphenidate [19–21].

On the other side of the spectrum, opioids also appear to disturb the normal sleep cycles. This is likely due to the interference of this class of molecules with the action or binding of sleeprelated neurotransmitters, such as noradrenaline, serotonin, acetyl choline, dopamine, histamine and gamma-aminobutyric acid [22]. Although this effect appears to be limited to the depth of sleep and duration of the REM (Rapid eye movement) phase rather than the quality of sleep itself [23, 24], this factor might be worth considering when opioid treatments worsen sleep disturbances derived from an underlying condition.

Constipation is also a common side effect reported in opioid users, due to the activation of mu receptors and the consequent modulation of gut motility [25]. Opioid-induced constipation is very diffused, with a single opioid treatment alone being able to induce constipation [26], this condition does not improve over time, and so its management should be planned in advance before the start of an opioid regimen. In recent studies, the naloxone-oxycodone combination has been shown to reduce constipation [25, 26], which favours an improved quality of life for patients.

Long-term use of opioids may also lead to additional complications, for example a hormonal imbalance [27, 28]. These ADRs are well known in the medical arena, to the point where the terms opioid endocrinopathy (OE) and opioid-induced androgen deficiency (OPIAD) both appear in the literature. Opioid users often display an imbalance in estrogen, testosterone, adrenocorticotropin, cortisol, and corticotropin-releasing hormone, luteinizing hormone, gonadotrophin-releasing hormone, dehydroepiandrosterone and dehydroepiandrosterone sulphates. This accounts for the increase reports of depression and sexual dysfunction among both sexes, while women are also at risk of a potential loss in bone mineral density [27, 28].

A well-known complication of opioid use is the potential development of physical addiction and opioid tolerance [29]. Both short- and long-term opioid use can induce these problems and due to the fact that they particularly affect chronic pain patients, incorrect use of opioids in this group of users could become both dangerous and ineffective.

Opioid tolerance is dependent on both the patient and the specific opioid employed [30]. This means that tolerance developed for a specific opioid does not automatically affect the efficacy of another opioid medication. However, in conjunction with the risk of hyperalgesia [31], which is, an increase in pain sensitivity also present in opioid users, this might still lead to an abuse of prescription medication, a particularly sensitive topic in opioid research.

Pruritus is another common adverse effect of opioids, more frequent with the parenteral route than oral. Opioid-induced pruritus is primarily mediated by mu-opioid receptors, serotonin receptors and to a lesser extent by histamine. The first-line treatment for pruritus should include low-dose nalbuphine, low-dose naloxone and ondansetron; antihistamines are less efficient. In addition to these common side effects, there are also ADRs for specific opioids. The most common ones are summarized in Table 1.


Table 1. Most commonly reported opioid-induced side effects [3].

To further reduce the ADRs caused by opioid administration, several measures have been suggested in the form of guidelines to ensure that an effort is being made on the part of the health care providers to reduce the amount of ADRs that occur with opioid drug administration.

The health care provider must ensure that before prescribing opioids to a patient, one has thoroughly documented the patient's diagnosis, medical well-being at the time and more importantly their psychological, psychiatric and social state, including whether or not the patient has abused any drugs in the past.

A patient who is now presenting with a pain condition should be asked questions regarding any previous medical or surgical treatments that may have been performed, along with clarifying and quantifying the present intensity of pain and how this may be affecting their daily activities of living.

Along with the patient's present physical state of health, a health care provider would also find it beneficial to inquire on the patient's living conditions, whether or not the patient has easy access to family and/or social support, and if the patient currently has a job or any domestic duties.

The psychiatric status of the patient is especially important. Knowing whether or not there has been a diagnosis of any psychiatric disorders in the past and how they were treated can greatly reduce the chances of the related ADRs or opioid addiction; some guidelines suggest to initiate with a low opioid dose and monitor the patient daily [32] when dealing with a patient who has a co-morbid psychiatric condition or a family history of psychiatric disorders.

Furthermore, substance use history is vital to formulate a comprehensive knowledge of the patient. A physician should inquire on the patient's history of substance use, abuse and addiction, namely marijuana, tobacco, benzodiazepines, opioids themselves, cocaine, amphetamines, barbiturates, hallucinogens and solvents.

receptors and to a lesser extent by histamine. The first-line treatment for pruritus should include low-dose nalbuphine, low-dose naloxone and ondansetron; antihistamines are less efficient. In addition to these common side effects, there are also ADRs for specific opioids.

> Nausea Vomiting

> Sweating

Headache Delirium/confusion Clouded vision Dizziness

Postural hypotension

Bladder dysfunction (e.g. urinary retention)

To further reduce the ADRs caused by opioid administration, several measures have been suggested in the form of guidelines to ensure that an effort is being made on the part of the health care providers to reduce the amount of ADRs that occur with opioid drug administration. The health care provider must ensure that before prescribing opioids to a patient, one has thoroughly documented the patient's diagnosis, medical well-being at the time and more importantly their psychological, psychiatric and social state, including whether or not the

A patient who is now presenting with a pain condition should be asked questions regarding any previous medical or surgical treatments that may have been performed, along with clarifying and quantifying the present intensity of pain and how this may be affecting their

Along with the patient's present physical state of health, a health care provider would also find it beneficial to inquire on the patient's living conditions, whether or not the patient has easy access to family and/or social support, and if the patient currently has a job or any domestic

The psychiatric status of the patient is especially important. Knowing whether or not there has been a diagnosis of any psychiatric disorders in the past and how they were treated can greatly reduce the chances of the related ADRs or opioid addiction; some guidelines suggest to initiate with a low opioid dose and monitor the patient daily [32] when dealing with a patient who has a co-morbid psychiatric condition or a family history of psychiatric

The most common ones are summarized in Table 1.

172 Pain Relief - From Analgesics to Alternative Therapies

Gastrointestinal Constipation

Neurologic Sedation/fatigue

Autonomic Xerostomia

Table 1. Most commonly reported opioid-induced side effects [3].

Cutaneous Pruritus

patient has abused any drugs in the past.

daily activities of living.

duties.

disorders.

After gathering all the information necessary to formulate a management plan, the physician should use this information to perform risk screening for the patient, assessing the potential for opioid drug misuse, overdose and addiction, looking at aberrant drug-related behaviours and if necessary, employing a urine drug screening.

Patients and their health care providers should then initiate goal setting in order to find out what the patient's goals are and how feasible the treatment could be, along with fully documenting what specific goals have been agreed on by the patient with the health care provider.

Additionally, documented informed consent for the use of opioids is suggesting, enabling the doctor and patient to explore the benefits, adverse effects. Medical complications and risks that may be encountered during the course of opioid treatment should also be determined and discussed with the patient, especially with high risk groups including the elderly, adolescent, pregnant, breastfeeding and those with co-morbid psychiatric conditions and those on longterm opioid treatment.

Moreover, one should verify and confirm that they have selected the most appropriate opioid for treatment of their patients, this should be done using peer-reviewed evidence which specifies which drug and what dose is used for first, second and third line treatment for the specific pain condition that the patient has.

After reviewing current data on the topic and starting a treatment regimen, one should continuously monitor the dose of opioid being given. If the patient is taking a dose on the higher end of the scale, the health care provider should re-asses the patient's pain condition to note if the medication is effective at reducing the pain (at least 30% reduction), and are there any non-opioid treatment options available.

Also, the doctor should clarify that all mental health disorders are adequately treated, that any ADRs are being managed and lastly if there is any sign of abnormal drug-related behaviours, the physician should then taper or switch the medication appropriately. After all these precautionary measures are taken, one should remember that arranging a consultation with an expert in pain or addiction management is always an option that could only benefit the patient greatly [33].

Health care providers should also consider alternative recommendations to replace longterm opioid treatment. Over the counter alternatives include acetaminophen and low dose NSAIDS. Although NSAIDs carry the well-known risk of organ failure and ulcer formation, NSAIDs at high doses are effective means of pain relief. Corticosteroids, serotonin inhibitors and norepinephrine inhibitors are all pharmacologic agents that can help alleviate pain.

Other measures which could be employed to reduce pain, with little to no risk to the patient, include the use of steroid injections for musculoskeletal pain, physical therapy, massage, exercise and chiropractic care [34].
