*4.1.4 Toxicity of NSAIDs*

In general, the use of non-steroidal and NSDAIDs in recommended therapeutic doses is well tolerated, but they contribute in various degrees to gastrointestinal (GI), renal and cardiovascular (CV) toxicity. In 2003 Schung SA and all [49] studied the efficacy and potential toxicity of opioids and non-opioids. They concluded that paracetamol used in therapeutic doses is safe, but an overdose is fatal, requiring specific treatment. The inhibition of the activity of COX-1 provokes impairment of gastric mucosa, renal parenchyma, and platelet function, manifesting several lifethreatening side effects. The most important are the development of gastrointestinal bleeding, asthma, renal dysfunction, hepatotoxicity, cardiotoxicity, and others.

There are general recommendations for the choice of NSAIDs in palliative medicine based on individual risk of GI or CV toxicity [50]. With the aim to avoid any GI risks, all patients on regular NSAIDs/COX-2 inhibitors -therapy, must receive proton pump inhibitors (**Table 2**).

NSAIDs used alone may not achieve its satisfactory effects; the combination of NSAIDs and step III opioids showed beneficial effect [38]. The essential drugs for palliative care are drugs that are effective for the treatment of common symptoms in palliative medicine, easily available, and are affordable, and are ones that correspond with the use of non-opioid drugs [51].


#### **Table 2.**

*Recommended NSAIDs therapy in patients with risks [32].*

## **4.2 Opioids**

They are particularly important medicines in PC for treatment and control of moderate to severe, acute, or chronic pain. Opioids are a group of medical agents that have opium or morphine –like properties with analgesic and many other pharmacological effects. In the past, their use was limited by the clinicians as undesirable drugs, especially in high doses, because of its possibility for addiction and appearance of several side effects, including respiratory depression.

Nowadays, as the population ages, with an increased prevalence of chronic pain, it has been agreed that this concern was unfounded. The new multimodal approach for pain control, the development of safer opioids analgesics and the use of opioids sparing agents, promise more regular prescription [42]. Cancer's intractable pain remains the most horrific condition where opioids take an eminent place in the treatment [43]. Concerning the ladder algorithm for severe pain, patients tailored therapy to its need, provides the right choice of opioids, non-opioids and adjuvant leading to more satisfactory pain relief [52].

Today it is accepted that opioids act on an endogenous opioidergic system which controls the nociception, and participates in modulation of other functions as autonomic, GI, endocrine or cognition. Exogenous opioids administered in the body have the affinity to bind with several distinct types of receptors for opioids. These receptors are the previously known G-protein-coupled receptors: "delta", "kappa" and "mu", which were named according to the exogenous ligand or tissue where they were isolated. By a recommendation from the International Union of Pharmacology (IUPHAR), in 2000 the opioid receptors were renamed to DOP, KOP and MOP [53].

The identification of the MOP receptors and the isolation of its protein helped in more profound study of the structure and pharmacological properties of morphine. The opioid receptors are found in peripheral and central nervous system including spinal cord (PNS & CNS). They are found also within vas deferens, GIT, heart, immune system, and knee joint. The endogenous opioids peptides, active ligands to the receptors, were identified in the brain extract, having analgesic properties similar as morphine, and known as "endogenous opioids". Endogenous opioids in CNS are derived from their precursors: pro-enkephalin, pro-opiomelanocortin, pro-dynorphin, and pre-pro-N/OFQ (pp-noc), and function as neurotransmitters important in control of hormone secretion, thermoregulation, and cardiovascular system [54]. The opioids' receptors are presented at **Table 3**.

The main event is in the CNS where, by the opioids activated MOP receptors, the descending inhibitory neurons producing opioids are activated –induced analgesia.

Opioids are divided upon its pharmaco-chemical origin in naturally occurring, semi-synthetic and synthetic compounds. According to their activity at opioids receptor, they are divided to agonists, partial agonists, and antagonists.

**231**

**Receptor& Precursor of endogenous ligand**

**Peptide-endogenous ligand**

**Effects**

**Clinical drugs**

**Agonists** Morphine Meperidine

Diamorphine Fentanyl/

Remifentanyl

Low Affinity; Fent/remifen–

no affinity

Low Affinity;

**Partial agonists**

Pentazocine

Buprenorphine

Butorphanol

Weak affinity

Low Affinity;

Buprenorphine

Butorphanol

Buprenorphine Low

Affinity;

**X** No Affinity

**Antagonists** Naloxone Butorphanol

Nalbuphine

**MOP** (POMC Unknown)

**DOP** Pro-enkephalin

**KOP** Pro-dynorphin

**NOP** Pre-pronociceptin

**Table 3.**

*Opioid receptors, endogenous ligands, and clinical drugs.*

N/OFQ

Dynorphin A/B

[Met]-enkephalin

Spinal/supraspinal analgesia, reduced gastric

[Leu]-enkephalin

motility

Spinal analgesia, dieresis, dysphoria

Spinally–analgesia, hyperalgesia&allodynia;

**X** No Affinity;

**X** No Affinity

Intracerabrovasular antianalgesic effect

β-Endorphin

Analgesia, sedation, nausea, vomiting,

reduction of gastric motylity

Endomorphin-1/2

*Multimodal Pain Management in the Setting of Palliative Care*

*DOI: http://dx.doi.org/10.5772/intechopen.96579*


*Multimodal Pain Management in the Setting of Palliative Care DOI: http://dx.doi.org/10.5772/intechopen.96579*

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

They are particularly important medicines in PC for treatment and control of moderate to severe, acute, or chronic pain. Opioids are a group of medical agents that have opium or morphine –like properties with analgesic and many other pharmacological effects. In the past, their use was limited by the clinicians as undesirable drugs, especially in high doses, because of its possibility for addiction

*Drugs Only GI problems CV problems/±GI CV/GI problems No CV/GI problems*

*Alternative therapy*

naproxen, ibuprofen,

diclofenac

*Avoid as possible* 

*or:* naproxen −1 g/24 h or ibuprofen 1.2 g/24 h

*Legend: GI-gastrointestinal; CV-cardiovascular; CV/GI – bough (gastrointestinal and cardiovascular).*

Nowadays, as the population ages, with an increased prevalence of chronic pain, it has been agreed that this concern was unfounded. The new multimodal approach for pain control, the development of safer opioids analgesics and the use of opioids sparing agents, promise more regular prescription [42]. Cancer's intractable pain remains the most horrific condition where opioids take an eminent place in the treatment [43]. Concerning the ladder algorithm for severe pain, patients tailored therapy to its need, provides the right choice of opioids, non-opioids and adjuvant

Today it is accepted that opioids act on an endogenous opioidergic system which controls the nociception, and participates in modulation of other functions as autonomic, GI, endocrine or cognition. Exogenous opioids administered in the body have the affinity to bind with several distinct types of receptors for opioids. These receptors are the previously known G-protein-coupled receptors: "delta", "kappa" and "mu", which were named according to the exogenous ligand or tissue where they were isolated. By a recommendation from the International Union of Pharmacology (IUPHAR), in 2000 the opioid receptors were renamed to DOP, KOP

The identification of the MOP receptors and the isolation of its protein helped in more profound study of the structure and pharmacological properties of morphine. The opioid receptors are found in peripheral and central nervous system including spinal cord (PNS & CNS). They are found also within vas deferens, GIT, heart, immune system, and knee joint. The endogenous opioids peptides, active ligands to the receptors, were identified in the brain extract, having analgesic properties similar as morphine, and known as "endogenous opioids". Endogenous opioids in CNS are derived from their precursors: pro-enkephalin, pro-opiomelanocortin, pro-dynorphin, and pre-pro-N/OFQ (pp-noc), and function as neurotransmitters important in control of hormone secretion, thermoregulation, and cardiovascular

The main event is in the CNS where, by the opioids activated MOP receptors, the descending inhibitory neurons producing opioids are activated –induced analgesia. Opioids are divided upon its pharmaco-chemical origin in naturally occurring, semi-synthetic and synthetic compounds. According to their activity at opioids receptor, they are divided to agonists, partial agonists, and antagonists.

system [54]. The opioids' receptors are presented at **Table 3**.

and appearance of several side effects, including respiratory depression.

leading to more satisfactory pain relief [52].

**230**

**4.2 Opioids**

**Table 2.**

*NSAIDs Avoid if possible, if is essential:*

Celecoxib 200 mg/24 h

*Recommended NSAIDs therapy in patients with risks [32].*

and MOP [53].

**Table 3.**

*Opioid receptors, endogenous ligands, and clinical drugs.*

Agonists are all opioid drugs which by binding to the receptors produce complete response morphine-like. Antagonists binding to the receptor have functional response and prevent binding of an agonist (naloxone). Partial agonists provide only partial functional response which is not corresponding to the amount of the drug [55].

According to the ladder algorithm, which is in use in palliative care centers, the opioids are divided upon their power in weak and strong opioids. In the following text, this classification will be taken in consideration.

#### *4.2.1 Weak opioids*

#### *4.2.1.1 Tramadol*

It is centrally acting non-opiate analgesic with low affinity for MOP receptors and is effective in the treatment of moderate to severe pain. It has modest affinity to MOR and has weak interaction with DOR and KOR receptors. Because of its non-opioid properties, it is included in bouts group as weak non opioid agent with centrally acting analgesic effect and is favorable for PC use. As it possesses MOR agonist properties, it also, through the activation of monoaminergic spinal inhibition of pain, acts in inhibition of the reuptake of serotonin and norepinephrine, which synergistically enhances its weak opioid mechanism of action [56].

Chemically tramadol is present in two isomers which separately (one or other) inhibit the reuptake of noradrenalin or serotonin. The activity of tramadol depends on its metabolic activation which differs among the patients. Its' use is convenient for treatment of acute and chronic pain, moderate and severe, from cancer and non–cancer origin, as diabetic neuropathy, and fibromyalgia as well.

Tramadol is found as tramadol hydrochloride in form of tablets or capsules (50 mg, and 100 mg) for oral use 4–6 times per day, and in injections of 2 ml (50 or 100 mg/ml) for IV, SC, IM and via spinal routes. The maximal daily dose is 400 mg which could be exceeded only in special clinical circumstances. Clinically used for moderate pain, can provoke some adverse reactions as, dizziness, nausea, sedation, dry mouth, sweating and gastrointestinal dysfunctions. It is an extremely popular drug used for pain relief in PC in musculoskeletal injuries and as postoperative analgesic drug.

#### *4.2.1.2 Codeine*

It is used as a weak opioid. It is a naturally occurring substance derived from opium (opiate) and is a pro-drug of morphine. Codeine is metabolized in the liver and is excreted through the urine. About 10% of codeine by demethylation is converted to morphine [57]. Codeine has incredibly low affinity to opioid receptors - 200 times lower than morphine; its analgesic property is due to converted morphine. Its dominant use is orally, in the form of tablets or suspensions, for control of mild to moderate pain, coughing and diarrhea. It is a drug with reliable effects, and particularly useful in PC for pain relief. It can be used alone or as a combination with some non-opioid drugs, which increases its analgesic profile. The onset of its effect is after 30 minutes, with maximum effect at two hours and its offset about four to six hours. It comes in form of tablets (15 mg, 30 mg and 60 mg), a liquid (25 mg/5 ml spoon) to swallow, and syrup (15 mg/5 ml) or as an injection-codeine phosphate - of 2 ml (60 mg/ml). The dose is repeated every 4 hours and should not exceed more than 4 times per day. The adverse effects of codeine are like all opioids: constipation, nausea, vomiting, drowsiness, lightheadedness, confusion, euphoria, vertigo, dry mouth, headaches, pruritus.

**233**

moving on to another opiate [60].

ness is necessary to be performed.

*Multimodal Pain Management in the Setting of Palliative Care*

and other which need an emergent resuscitation.

described above.

*4.2.2 Strong opioids*

*4.2.2.1 Morphine*

The safe treatment of codeine understands titration of the doses of codeine (starts with a small dose of the drug and gradually increases it, until a satisfied result of complete analgesia is obtained). Symptoms of overdoses of codeine are also like those of morphine and other opiate analgesics. They are miosis, sweating, cold skin, respiratory depression, bradycardia, hypotension, skeletal muscles flaccidity

**Hydrocodone** is a more potent synthetic opioid, hydrogenated ketone derivative of codeine. It is selective full agonists to MOP receptors. It is used for control of moderate to severe pain. It comes in form of tablets (5 mg and 10 mg) for oral use. Its duration of action is 4–5 h, and plasma half-life of 4 h. It is typically available in combination with acetaminophen or ibuprofen, which is very well suited for the treatment of mild to moderate pain syndromes in multimodal analgesia. In the past, hydrocodone has been used as a cough suppressant. For the treatment of severe chronic cancer pain, it has found a wide use with prolonged duration and the more potent metabolite hydromorphone [58]. As an agonist it poses all adverse reactions

Morphine is a strong naturally occurring opiate, isolated in 1805 from the poppy straw. Morphine is a "gold standard" among the opioids, against which the other drugs are measured in equal-analgesic doses. Morphine is a full MOP agonist with appreciable affinity to DOP and KOP. Its major effects are apperceived on parts of the CNS (posterior amygdala, hypothalamus, thalamus, nuscleus caudatus, putamen, and some cortical areas), producing drowsiness, analgesia, changes in the mood. MOP agonists further inhibit gastrointestinal tract (GIT) secretions and peristalsis; often causing constipation, also present is decreased bowel motility, vomit, nausea, and other sensations. MOP opioids also have effects on the cardiovascular system, thermoregulation, hormone secretion and immune function [59]. Morphine in PC is primarily used to treat acute and chronic severe pain and is a drug of first choice in PC for treatment of moderate to severe cancer pain. The oral formulation is easy for administration and especially useful for long treatment. It comes in form of tablets (30 mg, 60 mg, 100 mg), sub-lingual pastilles (60 mg), or as solution/suspensions (10 mg/5 ml). It is also valuable as injections (for IV, IM, SC, or PCA), rectal and spinal applications. In some countries extended-release capsules are present and extended-release tablets which are prescribed 1–2 times in 24 h. They are suitable for patients who are long time on morphine treatment. The onset of analgesic activity appears in 30 minutes, reaching the peak effect at 60–90 minutes. The average plasma half-life is 3 hours with offset of 6 h. The rest of morphine in plasma is present up to 15 hours [49]. The best way of the application of morphine is titrating of the doses. As it has no roof of its effect, the cure starts with small dose which may be increased by 30–50% every 12–24 hours until the optimal control of the pain. The titration continues to maximum tolerability, before

Proper dosing of morphine is especially important for elderly patients in PC institutions. They may be overly sensitive to the effects of morphine and a continuous monitoring of the respiration, blood pressure (BP) and the level of conscious-

The clinical use must be corresponding to the current recommendations at national or institutional levels. In most of the recommendations it has been shown that starting with a low-dose oral morphine (eg ≤30 mg/day) gives better pain

*DOI: http://dx.doi.org/10.5772/intechopen.96579*

*Multimodal Pain Management in the Setting of Palliative Care DOI: http://dx.doi.org/10.5772/intechopen.96579*

The safe treatment of codeine understands titration of the doses of codeine (starts with a small dose of the drug and gradually increases it, until a satisfied result of complete analgesia is obtained). Symptoms of overdoses of codeine are also like those of morphine and other opiate analgesics. They are miosis, sweating, cold skin, respiratory depression, bradycardia, hypotension, skeletal muscles flaccidity and other which need an emergent resuscitation.

**Hydrocodone** is a more potent synthetic opioid, hydrogenated ketone derivative of codeine. It is selective full agonists to MOP receptors. It is used for control of moderate to severe pain. It comes in form of tablets (5 mg and 10 mg) for oral use. Its duration of action is 4–5 h, and plasma half-life of 4 h. It is typically available in combination with acetaminophen or ibuprofen, which is very well suited for the treatment of mild to moderate pain syndromes in multimodal analgesia. In the past, hydrocodone has been used as a cough suppressant. For the treatment of severe chronic cancer pain, it has found a wide use with prolonged duration and the more potent metabolite hydromorphone [58]. As an agonist it poses all adverse reactions described above.

#### *4.2.2 Strong opioids*

#### *4.2.2.1 Morphine*

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

text, this classification will be taken in consideration.

drug [55].

*4.2.1 Weak opioids*

*4.2.1.1 Tramadol*

analgesic drug.

*4.2.1.2 Codeine*

Agonists are all opioid drugs which by binding to the receptors produce complete response morphine-like. Antagonists binding to the receptor have functional response and prevent binding of an agonist (naloxone). Partial agonists provide only partial functional response which is not corresponding to the amount of the

According to the ladder algorithm, which is in use in palliative care centers, the opioids are divided upon their power in weak and strong opioids. In the following

It is centrally acting non-opiate analgesic with low affinity for MOP receptors and is effective in the treatment of moderate to severe pain. It has modest affinity to MOR and has weak interaction with DOR and KOR receptors. Because of its non-opioid properties, it is included in bouts group as weak non opioid agent with centrally acting analgesic effect and is favorable for PC use. As it possesses MOR agonist properties, it also, through the activation of monoaminergic spinal inhibition of pain, acts in inhibition of the reuptake of serotonin and norepinephrine, which synergistically enhances its weak opioid mechanism of action [56].

Chemically tramadol is present in two isomers which separately (one or other) inhibit the reuptake of noradrenalin or serotonin. The activity of tramadol depends on its metabolic activation which differs among the patients. Its' use is convenient for treatment of acute and chronic pain, moderate and severe, from cancer and

Tramadol is found as tramadol hydrochloride in form of tablets or capsules (50 mg, and 100 mg) for oral use 4–6 times per day, and in injections of 2 ml (50 or 100 mg/ml) for IV, SC, IM and via spinal routes. The maximal daily dose is 400 mg which could be exceeded only in special clinical circumstances. Clinically used for moderate pain, can provoke some adverse reactions as, dizziness, nausea, sedation, dry mouth, sweating and gastrointestinal dysfunctions. It is an extremely popular drug used for pain relief in PC in musculoskeletal injuries and as postoperative

It is used as a weak opioid. It is a naturally occurring substance derived from opium (opiate) and is a pro-drug of morphine. Codeine is metabolized in the liver and is excreted through the urine. About 10% of codeine by demethylation is converted to morphine [57]. Codeine has incredibly low affinity to opioid receptors - 200 times lower than morphine; its analgesic property is due to converted morphine. Its dominant use is orally, in the form of tablets or suspensions, for control of mild to moderate pain, coughing and diarrhea. It is a drug with reliable effects, and particularly useful in PC for pain relief. It can be used alone or as a combination with some non-opioid drugs, which increases its analgesic profile. The onset of its effect is after 30 minutes, with maximum effect at two hours and its offset about four to six hours. It comes in form of tablets (15 mg, 30 mg and 60 mg), a liquid (25 mg/5 ml spoon) to swallow, and syrup (15 mg/5 ml) or as an injection-codeine phosphate - of 2 ml (60 mg/ml). The dose is repeated every 4 hours and should not exceed more than 4 times per day. The adverse effects of codeine are like all opioids: constipation, nausea, vomiting, drowsiness, lightheadedness, confusion, euphoria, vertigo, dry

non–cancer origin, as diabetic neuropathy, and fibromyalgia as well.

**232**

mouth, headaches, pruritus.

Morphine is a strong naturally occurring opiate, isolated in 1805 from the poppy straw. Morphine is a "gold standard" among the opioids, against which the other drugs are measured in equal-analgesic doses. Morphine is a full MOP agonist with appreciable affinity to DOP and KOP. Its major effects are apperceived on parts of the CNS (posterior amygdala, hypothalamus, thalamus, nuscleus caudatus, putamen, and some cortical areas), producing drowsiness, analgesia, changes in the mood. MOP agonists further inhibit gastrointestinal tract (GIT) secretions and peristalsis; often causing constipation, also present is decreased bowel motility, vomit, nausea, and other sensations. MOP opioids also have effects on the cardiovascular system, thermoregulation, hormone secretion and immune function [59].

Morphine in PC is primarily used to treat acute and chronic severe pain and is a drug of first choice in PC for treatment of moderate to severe cancer pain. The oral formulation is easy for administration and especially useful for long treatment. It comes in form of tablets (30 mg, 60 mg, 100 mg), sub-lingual pastilles (60 mg), or as solution/suspensions (10 mg/5 ml). It is also valuable as injections (for IV, IM, SC, or PCA), rectal and spinal applications. In some countries extended-release capsules are present and extended-release tablets which are prescribed 1–2 times in 24 h. They are suitable for patients who are long time on morphine treatment. The onset of analgesic activity appears in 30 minutes, reaching the peak effect at 60–90 minutes. The average plasma half-life is 3 hours with offset of 6 h. The rest of morphine in plasma is present up to 15 hours [49]. The best way of the application of morphine is titrating of the doses. As it has no roof of its effect, the cure starts with small dose which may be increased by 30–50% every 12–24 hours until the optimal control of the pain. The titration continues to maximum tolerability, before moving on to another opiate [60].

Proper dosing of morphine is especially important for elderly patients in PC institutions. They may be overly sensitive to the effects of morphine and a continuous monitoring of the respiration, blood pressure (BP) and the level of consciousness is necessary to be performed.

The clinical use must be corresponding to the current recommendations at national or institutional levels. In most of the recommendations it has been shown that starting with a low-dose oral morphine (eg ≤30 mg/day) gives better pain

relief than using weak opioids. National Institute for Heath and Care Excellence, UK, (NICE) [61] in its Guidelines recommends that morphine should be used as first-line oral opioid for relief of cancer pain. It is also recommended for children with cancer pain; in the guidelines of the Royal Children's Hospital Melbourne, it is advised the use of oral morphine for children over six months with start dose of 0.2–0.5 mg/kg/dose, every 4-6 h orally [32].

The adverse effects of morphine include sedation, cognitive impairment, nausea and vomiting which are frequently seen. Also seen are respiratory depression, etching, circulatory disturbances, hormonal imbalance with hypogonadism, immunodeficiency, changes in the mood with hallucinations and depression. Constipation is seen with chronic therapy; patients do not develop tolerance to it and typically require preemptive treatment with laxatives. Also seen are tolerance or intolerance to morphine and addiction. The genetic approach confirms that those effects of morphine are result of the action at the MOP receptor and N/OFQ–NOP system [62, 53].

Many opioids are made by the modification of the morphine molecule, as Apomorphine, Oxycodone, Hydromorphone. They have similar properties as morphine and only the specificity of their use in PC will be mentioned.

**Oxycodone–**is a synthetic opioid, with high selective affinity to MOP and low affinity to DOP and KOP receptors, working as typical agonist. It is used for treatment of moderate to severe pain, is metabolized hepatically to the active oxymorphone [63]. It comes in form of tablets with immediate and controlled release of action or in injection. The onset of the analgesic effect starts within 15 minutes and it is used widely as analgesics especially for postoperative pain. One study compared the controlled-release oxycodone and morphine tablets in 45 cancer patients and was found that both were transformed in liver to the active oxymorphone. Oxycodone was the most often used drug in USA in the last two decades and was responsible for the "opioid crisis" due to – "too much free use" of this drug [64]. It is a particularly good pain killer and because of its oral application it is recommended for patients at PC. It develops the same side effects as other morphine like drugs.

**Hydromorphone**- is a water-soluble opioid that is several times more potent than morphine allowing for smaller dosage. It is found in parenteral, rectal, subcutaneous, and oral formulations. It is also used for epidural and intrathecal administration for postoperative pain relief or when other ways are not appropriate [65]. It was shown more effective pain relief properties for continuous dull pain and provides superior analgesia when is mixed with epinephrine.

**Meperidine**- is a synthetic analgesic drug indicated for the treatment of moderate to severe pain. It is delivered as hydrochloride salt found in form of tablets (50 and 100 mg), emulsion, or injections. It is predominantly a MOP agonist with main action on CNS and the bowel. Its analgesic effects exceed after 15 minutes and the peak effect after 45 minutes. The effectiveness of parenteral application is the same as that of morphine. The adverse reactions are like those of other agonists [63].

**Methadone**- is synthetic opioid, MOP agonist, which is used for pain relief in PC. Its pharmacological profile is like that of morphine, but it has a very long half-life with considerably longer duration of action. It is also an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor [64]. Methadone is without any active metabolites but is found as racemic mixture of 2 enantiomers; the R- methadone is responsible for analgesic effects, while S-methadone is a NMDA antagonist. It has little tendency to induce tolerance in patients, which makes it suitable drug for treatment of opioid dependence. It has unique properties that make it useful in treating pain which is poorly controlled by other opioids. Its dosing is flexible, although it can be used in neuropathic and somatic pain relief. It is safe for patients

**235**

500 mg/24 h.

more potent opioid.

*Multimodal Pain Management in the Setting of Palliative Care*

with renal impairment and is only long-acting liquid opioid. As a result of the lack of knowledge of its metabolic changes, it has possible interactions with other drugs, and its' long half-life made, methadone is seen to be an incriminated drug [59].

acting drug which is 70 to 100 times more potent than IV morphine.

choice in control of breakthrough cancer pain (BTcP) [67].

phine (5 mcg/h) is suitable for opioid naive patients.

epidural space provide prolonged postoperative analgesia up to 8 hours [50].

**Fentanyl-**is a synthetic powerful opioid, related to phenyl piperidine family that includes sufentanil, alfentanyl and remifentanil, with similar properties to the other opioids, selective MOP agonists. It is a powerful analgesic, lipophylic opioid, quick

Fentanyl is used for treatment of severe acute and chronic pain, as a medicine for anesthesia, for postoperative pain relief and in the treatment of intractable cancer pain in PC. It is available in parenteral, transmucosal, and transdermal formulations. Intravenous fentanyl has very rapid onset of action 5 minutes to peak analgesia, with offset of two hours. Fentanyl and its forms administered in intrathecal and

Because of the variety of forms, fentanyl has become the most widely used drug in palliative medicine. It is found in form of fentanyl buccal soluble film (FBSF), fentanyl buccal tablets (FBT), fentanyl pectin nasal spray (FPNS), oral transmucosal fentanyl citrate (OTFC), intranasal fentanyl spray (INFS), sublingual fentanyl and transdermal patches (FTP) [66]. Most of those forms are extremely valuable for analgesia of patients whose oral access is compromised, or with existence of profuse nausea and vomiting, limiting the swallowing of the required dose of opioid. The lowest transdermal dose of patch currently available is 2.5 mg which delivers 25 mcg/h of transdermal fentanyl. Due to its quick effect, Fentanyl is the drug of

**Buprenorphine** - is a semi-synthetic highly lipophilic opioid. It has partial MOP

agonist properties and has been in clinical use for over 25 years for treatment of acute and chronic pain [63]. Recent studies have confirmed that buprenorphine binds with high affinity to MOP and KOP opioid receptors, and with relatively lower affinity to DOP receptors. It is found in several formulations for parenteral, sublingual, and transdermal use. It is also used as supplement to anesthesia and for psychiatric disorders (treatment of opioid addiction). Now Buprenorphine is widely used for cancer pain management. There is still debate about the potential damage of the transdermal patch and most of the authors think that because of this reason it is not suitable for PC [68]. As an opioid, a respiratory depression could occur, but it does not response to naloxone. The lowest patch strength of buprenor-

**Tapentadol** is a new, centrally acting analgesic agent approved in Europe in 2010, used for treatment of acute and chronic, moderate to severe pain. Its molecular structure is chemically like tramadol. It has a dual mode of action, as a MOP agonist and a norepinephrine reuptake inhibitor. This metabolic change makes it a

Its potency is somewhere between tramadol and morphine, like hydrocodone, oxycodone, and meperidine with more tolerable side effects profile [58–60]. Its formulation is in a form of tablets and solutions; tablets for immediate release (IR) of 50 mg, 75 mg, and 100 mg, are indicated for treatment of acute to moderate pain, with maximum toxic dose of 700 mg/day. For treatment of chronic pain, it is advised to use tablets with extended release (50 mg, 100 mg, 150 mg, 200 mg, and 250 mg). This formulation for long-release, with once-daily dosing of Tapentadol is especially acceptable for treatment in PC of chronic severe pain because of its simple use and more powerful effect [69]. The daily dose must not exceed

Clinical studies show that tapentadol is efficient pain reliever in various pain settings including PC setting. In a Clinical trial (NCT01500317) where the adverse effects of tapentadol with the equivalent doses of oxycodon were compared,

*DOI: http://dx.doi.org/10.5772/intechopen.96579*

#### *Multimodal Pain Management in the Setting of Palliative Care DOI: http://dx.doi.org/10.5772/intechopen.96579*

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

0.2–0.5 mg/kg/dose, every 4-6 h orally [32].

MOP receptor and N/OFQ–NOP system [62, 53].

relief than using weak opioids. National Institute for Heath and Care Excellence, UK, (NICE) [61] in its Guidelines recommends that morphine should be used as first-line oral opioid for relief of cancer pain. It is also recommended for children with cancer pain; in the guidelines of the Royal Children's Hospital Melbourne, it is advised the use of oral morphine for children over six months with start dose of

The adverse effects of morphine include sedation, cognitive impairment, nausea and vomiting which are frequently seen. Also seen are respiratory depression, etching, circulatory disturbances, hormonal imbalance with hypogonadism, immunodeficiency, changes in the mood with hallucinations and depression. Constipation is seen with chronic therapy; patients do not develop tolerance to it and typically require preemptive treatment with laxatives. Also seen are tolerance or intolerance to morphine and addiction. The genetic approach confirms that those effects of morphine are result of the action at the

Many opioids are made by the modification of the morphine molecule, as Apomorphine, Oxycodone, Hydromorphone. They have similar properties as morphine and only the specificity of their use in PC will be mentioned.

than morphine allowing for smaller dosage. It is found in parenteral, rectal, subcutaneous, and oral formulations. It is also used for epidural and intrathecal administration for postoperative pain relief or when other ways are not appropriate [65]. It was shown more effective pain relief properties for continuous dull pain and

**Meperidine**- is a synthetic analgesic drug indicated for the treatment of moderate to severe pain. It is delivered as hydrochloride salt found in form of tablets (50 and 100 mg), emulsion, or injections. It is predominantly a MOP agonist with main action on CNS and the bowel. Its analgesic effects exceed after 15 minutes and the peak effect after 45 minutes. The effectiveness of parenteral application is the same as that of morphine. The adverse reactions are like those

**Methadone**- is synthetic opioid, MOP agonist, which is used for pain relief in PC. Its pharmacological profile is like that of morphine, but it has a very long half-life with considerably longer duration of action. It is also an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor [64]. Methadone is without any active metabolites but is found as racemic mixture of 2 enantiomers; the R- methadone is responsible for analgesic effects, while S-methadone is a NMDA antagonist. It has little tendency to induce tolerance in patients, which makes it suitable drug for treatment of opioid dependence. It has unique properties that make it useful in treating pain which is poorly controlled by other opioids. Its dosing is flexible, although it can be used in neuropathic and somatic pain relief. It is safe for patients

provides superior analgesia when is mixed with epinephrine.

**Oxycodone–**is a synthetic opioid, with high selective affinity to MOP and low affinity to DOP and KOP receptors, working as typical agonist. It is used for treatment of moderate to severe pain, is metabolized hepatically to the active oxymorphone [63]. It comes in form of tablets with immediate and controlled release of action or in injection. The onset of the analgesic effect starts within 15 minutes and it is used widely as analgesics especially for postoperative pain. One study compared the controlled-release oxycodone and morphine tablets in 45 cancer patients and was found that both were transformed in liver to the active oxymorphone. Oxycodone was the most often used drug in USA in the last two decades and was responsible for the "opioid crisis" due to – "too much free use" of this drug [64]. It is a particularly good pain killer and because of its oral application it is recommended for patients at PC. It develops the same side effects as other morphine like drugs. **Hydromorphone**- is a water-soluble opioid that is several times more potent

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of other agonists [63].

with renal impairment and is only long-acting liquid opioid. As a result of the lack of knowledge of its metabolic changes, it has possible interactions with other drugs, and its' long half-life made, methadone is seen to be an incriminated drug [59].

**Fentanyl-**is a synthetic powerful opioid, related to phenyl piperidine family that includes sufentanil, alfentanyl and remifentanil, with similar properties to the other opioids, selective MOP agonists. It is a powerful analgesic, lipophylic opioid, quick acting drug which is 70 to 100 times more potent than IV morphine.

Fentanyl is used for treatment of severe acute and chronic pain, as a medicine for anesthesia, for postoperative pain relief and in the treatment of intractable cancer pain in PC. It is available in parenteral, transmucosal, and transdermal formulations. Intravenous fentanyl has very rapid onset of action 5 minutes to peak analgesia, with offset of two hours. Fentanyl and its forms administered in intrathecal and epidural space provide prolonged postoperative analgesia up to 8 hours [50].

Because of the variety of forms, fentanyl has become the most widely used drug in palliative medicine. It is found in form of fentanyl buccal soluble film (FBSF), fentanyl buccal tablets (FBT), fentanyl pectin nasal spray (FPNS), oral transmucosal fentanyl citrate (OTFC), intranasal fentanyl spray (INFS), sublingual fentanyl and transdermal patches (FTP) [66]. Most of those forms are extremely valuable for analgesia of patients whose oral access is compromised, or with existence of profuse nausea and vomiting, limiting the swallowing of the required dose of opioid. The lowest transdermal dose of patch currently available is 2.5 mg which delivers 25 mcg/h of transdermal fentanyl. Due to its quick effect, Fentanyl is the drug of choice in control of breakthrough cancer pain (BTcP) [67].

**Buprenorphine** - is a semi-synthetic highly lipophilic opioid. It has partial MOP agonist properties and has been in clinical use for over 25 years for treatment of acute and chronic pain [63]. Recent studies have confirmed that buprenorphine binds with high affinity to MOP and KOP opioid receptors, and with relatively lower affinity to DOP receptors. It is found in several formulations for parenteral, sublingual, and transdermal use. It is also used as supplement to anesthesia and for psychiatric disorders (treatment of opioid addiction). Now Buprenorphine is widely used for cancer pain management. There is still debate about the potential damage of the transdermal patch and most of the authors think that because of this reason it is not suitable for PC [68]. As an opioid, a respiratory depression could occur, but it does not response to naloxone. The lowest patch strength of buprenorphine (5 mcg/h) is suitable for opioid naive patients.

**Tapentadol** is a new, centrally acting analgesic agent approved in Europe in 2010, used for treatment of acute and chronic, moderate to severe pain. Its molecular structure is chemically like tramadol. It has a dual mode of action, as a MOP agonist and a norepinephrine reuptake inhibitor. This metabolic change makes it a more potent opioid.

Its potency is somewhere between tramadol and morphine, like hydrocodone, oxycodone, and meperidine with more tolerable side effects profile [58–60]. Its formulation is in a form of tablets and solutions; tablets for immediate release (IR) of 50 mg, 75 mg, and 100 mg, are indicated for treatment of acute to moderate pain, with maximum toxic dose of 700 mg/day. For treatment of chronic pain, it is advised to use tablets with extended release (50 mg, 100 mg, 150 mg, 200 mg, and 250 mg). This formulation for long-release, with once-daily dosing of Tapentadol is especially acceptable for treatment in PC of chronic severe pain because of its simple use and more powerful effect [69]. The daily dose must not exceed 500 mg/24 h.

Clinical studies show that tapentadol is efficient pain reliever in various pain settings including PC setting. In a Clinical trial (NCT01500317) where the adverse effects of tapentadol with the equivalent doses of oxycodon were compared,

tapentadol reported significantly lower incidence of GI side effects [70]. Its characteristics offer an improvement in pain therapy, and easier coping with severe pain for PC patients.

The described side effects are like those of other opioids- such as development of allergy, nausea, vomiting, and loss of appetite; dizziness, worsening tiredness or weakness may be seen in some consumers. Overdose, addicting, and abstention syndrome are also present with an inappropriate use of the drug.

"*Breakthrough cancer pain*" (BTcP) - is a state of chronic pain with adequate analgesia where a temporal intensive peak pain occurs, interrupting the state of controlled pain. Traditionally the patients with cancer pain were treated with oral opioids, but for the treatment of BTcP it is recommended the fast-realizing forms of fentanyl (FPNS or INFS). Some authors reported good response to short-acting immediate-release (IR) oral opioid in advanced cancer, supporting the use of these opioids in clinical practice [67]. In this context, the National Institute for Health and Care Excellence guidelines do not recommend transdermal opioids as a firstline treatment, when oral opioids are appropriate, specifically fentanyl formulations, are now the gold standard for BTcP due to rapid action and high efficacy.

#### *4.2.2.2 Side effects of the use of morphine and morphine like opioids*

The development of constipation, nausea and vomiting; delirium, hallucinations, sedation, myoclonus, hyperalgesia, seizures, headaches, euphoria, or dysphoria are often seen as adverse reaction to morphine like opioids. Respiratory depression or non-cardiogenic pulmonary edema can appear. Pruritus, urinary retention and altered renal function may be seen also, and signs from CV system as bradycardia and hypotension as well, hypogonadism, sexual dysfunction, osteoporosis and impairment in the immune system, physical dependence, and the tolerance to the drugs [71].

In most of the Guidelines for PC is emphasized that during the pain management at the end of life, addiction should not be an issue [61, 72, 73]. It is also reported that development of life-threatening overdoses of morphine and morphine like opioids in palliative setting is exceedingly rare. In 2005, the American Assembly of Nurses referred that overdoses may be avoided with rational prescribing of opioids, proper conversion to other drugs, titration and use of adjuvant analgesics [74, 75]. The proper titration of opioids and multimodal approach with the use of other techniques such as radiotherapy, bisphosphonates, and other medicines in [76] Ca pain management, or increased dose of current analgesics, and adding adjuvants analgesic for neuropathic pain, may help patients in PC to easier cope with severe pain without a danger for overdoses.

At the commencement of therapy with opioids, sedation and drowsiness appeared, which are common side effects of opioids. The use of light stimulants such as caffeine, or methylphemidate [32] may be helpful. Other mental dysfunctions such as euphoria, dysphoria or nightmares need some additional treatment.

The main sign of overdose with morphine and morphine like opioids, besides drowsiness, is the appearance of respiratory depression (respiratory rate - RR < 8/ min, SpO2 < 90% and cyanosis). Because of the progression of the main disease, the respiration at the end of the life could be slow, shallow, and noisy, what may be misunderstood as a respiratory depression. The recommendations proposed by the North East London Cancer Network (NHS)-2018, did not advise immediate use of antagonist naloxone for treatment of respiratory depression. The reason for that is the ability of naloxone to break the optimal analgesia and produce a "pain crisis" which is distressing for the patient and the family [77].

It is advised to use a conservative protocol for such events, which is as follows:

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*Multimodal Pain Management in the Setting of Palliative Care*

hemodynamic instability, hypotension until shock and death [63].

steroids, NMDA receptor antagonists and others [78].

bone marrow: suppression is possible to develop.

bone fractures, osteoporosis with past fracture, etc.

If the patient with slow RR (8/min) is not dying, has no cyanosis and is rousable, the measure "wait and observe" must be performed. If the RR decreases (<8/min), the patient is unconscious, cyanotic with SpO2 < 90% and tachycardia, opioids should be stopped and an oxygenation via mask should be administered. The treatment compromises of emergent resuscitation and application of MOP antagonist, naloxone. Naloxone (0.4 mg/ml) is given as a diluted solution of 0.04 mg/ml. The start of the application is with 0.5 ml of diluted solution (0.02 mg), and this dose is repeated until higher responsiveness is obtained [65]. If the patient is not treated, the respiratory depression can cross to respiratory arrest, with hypoxia, cyanosis,

They are drugs with indications different than analgesia. Today is known that adjuvants in combination with some analgesic drugs produce efficient analgesia. In use are several groups of medicines: antidepressants, antiepileptic drugs, cortico-

The *tricyclic antidepressants* (TCA) adjuvant agents are very well accepted by patients with cancer pain due to their positive effects on the mood and sleep. Amitriptyline 1–2 mg/kg oral is a useful agent for treatment of children with nocturnal pain, neuropathic pain or sleeping difficulties. Amitriptyline, imipramine, doxepin, and clomipramine are also useful and attractive drugs for MMA of the patients in PC and for treatment of neuropathic pain. Because of common side effects of TCA, is advised the use of *Nontricyclic* compounds as safer [79]. Some authors suggest that the use of secondary amines desipramine and nortriptyline, are less anticholinergic and could be better tolerated than tertiary amines [80]. It has been also shown that trazadone, a nontricyclic antidepressant, has the same effec-

*Antiepileptic* drugs (AED) can offer a remarkably effective treatment strategy in combination with opioids and non-opioids in MMA. It has been proposed that pregabalin and gabapentin, which are effective in neuropathic pain, target accessory α2δ subunits of Ca2+ channels. An alternative mechanism of action has also been suggested - that additionally gabapentin blocks spine morphogenesis [82]. The initial daily dose of 100–300 mg of gabapentin can be increased every 3 days. The usual maximum dose is 3600 mg daily. It was reported that carbamazepine, lamotrigine, levetiracetam have been efficacious in alleviating different neuropathic pain syndromes and cancer pain. Precautions must be taken at liver function and

*Corticosteroids* are frequently used in PC as an adjuvant therapy for cancer related pain syndromes, which include bone pain, neuropathic pain from infiltration or metastatic compression of neural structures, headache due to increased intracranial pressure, or if the pain is from inflammatory origin (nerve, bone). If the pain is aggravated by tension or muscle spasms, the use of muscle relaxants can play an important role in relieving the pain [83], sedation and anti-cholinergic are

*Bisphosphonates*as adjuvant can help control the pain in certain situations such as: cancer-related neuropathic pain [84], in prevention of fractures in people whose cancer has spread to the bone, in metastatic bone pain, bone pain, breast cancer,

*NMDA antagonists* has been shown that play an important place and are efficient modulators of the pain in postoperative allodynia and hyperalgesia. A representative of this group is *Ketamine,* a dissociative anesthetic which is used for analgesia as

well. It produces, sedation, amnesia, and as an adjuvant sufficient analgesia.

*DOI: http://dx.doi.org/10.5772/intechopen.96579*

**4.3 Adjuvant analgesics**

tiveness as amitriptyline [81].

present as side effects.

If the patient with slow RR (8/min) is not dying, has no cyanosis and is rousable, the measure "wait and observe" must be performed. If the RR decreases (<8/min), the patient is unconscious, cyanotic with SpO2 < 90% and tachycardia, opioids should be stopped and an oxygenation via mask should be administered. The treatment compromises of emergent resuscitation and application of MOP antagonist, naloxone. Naloxone (0.4 mg/ml) is given as a diluted solution of 0.04 mg/ml. The start of the application is with 0.5 ml of diluted solution (0.02 mg), and this dose is repeated until higher responsiveness is obtained [65]. If the patient is not treated, the respiratory depression can cross to respiratory arrest, with hypoxia, cyanosis, hemodynamic instability, hypotension until shock and death [63].
