**4.1 Non-opioids**

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

Increased Plasma Cortisol Categorical Scale Increased Plasma Catecholamine's Numerical Scale Cardio-Circulatory Changes (Pulse, BP, CVP) Visual Analog Scale

Respiratory Changes (RR, VC, FEV, TV)

Inverse Correlation with Plasma Beta Endorphins

Tears, Facial grimacing

Changes in Dermal Temperature

**Type I – PAIN EVALUATION Type II – PAIN EVALUATION PHYSIOLOGICAL CHANGES ONE DIMENSIONAL METHODS**

**NEUROPHARMACOLOGICAL MULTI DIMENSIONAL METHODS**

**NEUROLOGICAL** Dartmaut' Questionnaire Changes in Nervous Conductance Velocity List of West Haven-Yale Evoked potential (neurologic dysfunctions) Pain perception profile Micro- neurographics Behavior observation

Mc GILL Questionnaire

Pain Diary Pain Scoring Prevocational Test Rehabilitation Test

A simple observation can discover any kind of discomfort, lack of interest, anxiety, crying, tears, abnormal position or movement, or changes in vital parameters as high blood pressure, tachycardia, sweating, impairment in dieresis and other [30].

*Legend: BP-blood pressure; CVP-central venous pressure; RR-respiratory rate; VC-vital capacity. FEV-forcefully* 

In the *preparation of the treatment plan,* it must be considered that pain is a syndrome with neuropathic, nociceptive, emotional, and psycho-social overlays and it can be used to guide an individually tailored treatment plan because of its subjective nature. To improve outcomes, it is necessary to integrate the PC with other settings [33]. Patient / family must be involved in the planning of the pain treatment. The common problems in planning appear from the conservative believes and myths about pain. The existence of the pain is inevitable at the end of the life; the patient/family has fears about the use of opioids because of addiction and side effects. For this reason, is necessary to discuss the management strategy for pain relief. All parties must be very well informed about the multimodal approach and the incorporation of the interdisciplinary team in pain management that comprises integration of the use of medicines, physical therapy, music, meditation, hypnotherapy, and others alternative methods. Additionally, the personal abilities of the patient/family regarding the terminal stage, culture, religion, and other socio-economic factor must be taken in consideration.

The pain services as special teams working on pain treatment takes place in or out of the Hospices. They could practice pain treatment as "patronage services",

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**3.4 Pain services**

**3.3 Treatment plan**

*The evaluation of pain [4].*

**Table 1.**

*expired volume; TV-tidal volume*.

Non –opioids are a group of medications consisting of anti-inflammatory and non-steroidal anti-inflammatory drugs. They have antipyretic, anti-inflammatory, and anti-platelet effects. Their use in palliative care takes an eminent place because most of the etiological factors of the pain are related to inflammation. Traditionally they include anti-inflammatory drugs such as salicylic acid, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs), which remain the major players for the treatment of pain in PC [38]. They have an opioid sparing effect when used in multimodal therapeutic approach (see below).

#### **Figure 1.**

*Readapted WHO ladder for analgesic management [22]. (legend: NSAIDs- non-steroidal anti-inflammatory drugs; PCA- patient control analgesia).*

## *4.1.1 Anti-inflammatory drugs*

**Acetaminophen** (paracetamol) chemically belongs to para-aminophenol derivatives; it is an active metabolite of phenacetin with an analgesic-antipyretic property and weak anti-inflammatory activity. It is recommended as a first step analgesic for mild to moderate pain [39]. Its mechanism of action is based to inhibition of central prostaglandin synthesis in the central nervous system and possible increases of noradrenaline in CNS and peripheral beta-endorphins [40]. It describes its analgesic and antipyretic activity without any effects on inflammation. Its use in PC is crucial on its formulations in form of tablets, coated tablets, or ampoules; therefore, it can be administered orally or IV. The onset of action for oral form is slow (15 min), so the use of intravenous application is the more appropriate. The maximum recommended therapeutic dose is 4000 mg/24 h, or 80/kg BW/24 h. According to a Meta analyses made from Schüchen RH et al. (2018), it was shown that there was no conclusive evidence that Acetaminophen in treatment of cancer pain produces satisfactory pain relief [41], but often it is used in combinations with opioids and it shows a decrease of the need for opioids (spearing effect). Its metabolites contribute to the toxic effects, so doses over its maximum dosage provoke liver damage. Therefore, it must be used with precaution in patients with liver diseases.

**Aspirin** (acetylsalicylic acid) chemically belongs to the group of salicylates [42]. It is the most widely used drug for the treatment of mild to moderate pain. Aspirin has an analgesic-antipyretic, anti-inflammatory effect and prevents clotting. It is usually used for pain relief with low intensity. Its mode of action is through the decreased production of prostaglandins and thromboxane A2 by an irreversible inactivation of the ciclooxygenase enzymes (COX). It is an important additional medicine for patients with severe inflammatory pain (rheumatoid arthritis and similar). It is suitable for long-term use, because it is safe, with lower toxicity than paracetamol or opioids. In PC it can be safety used for pain control of acute pain, such as headache, toothache, minor back pain, for prophylaxis of myocardial infarction due to its well-established anti-platelet action. Its formulation is prepared in tablets and suppositories (100 mg, 300 mg, and 500 mg). Its use is 4–6 times per day, with maximum dose of 3000 mg/24 h. Among its side effects, the most important are appearance of peptic ulcer, allergy to salicylates and development of Reye's syndrome, if it is used in children younger than 16 years old. Overdosed, aspirin can cause cardiovascular instability, exacerbate underlying renal insufficiency, and even lead to coma with renal failure, metabolic acidosis, and respiratory arrest [42].

#### *4.1.2 Non-steroidal anti-inflammatory drugs*

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of potent analgesics, antipyretics, and anti-inflammatory agents which are efficient in reliving of moderate to severe pain from musculoskeletal origin. They are widely in use at the institutions of palliative care as mono or combined therapy. The list of NSAID medicines is long and, in this document, only the most often used drugs will be mentioned. The NSAIDs mode of action is through peripheral and central inhibition of prostaglandin production from arachidonic acid through acetylating of two cyklooxygenase isoenzymes (COX-1 and/or COX-2). The nonselective NSAIDs inhibit the activity of both cyklooxygenase - COX-1 and COX-2. The most often used non-selective NSAIDs are ibuprofen, ketonal, diclophenac, naproxen, etc. [43].

On the other side, the selective inhibitors to isoenzyme COX-2 (celecoxib, valdecoxib and rofecoxib) have the same analgesic effects as the non-selective NSAIDs,

**229**

to 6 days [48].

*4.1.4 Toxicity of NSAIDs*

proton pump inhibitors (**Table 2**).

respond with the use of non-opioid drugs [51].

*Multimodal Pain Management in the Setting of Palliative Care*

but with a reduced risk for gastrointestinal tract (GIT) and platelets that makes those acceptable for pain management [44]. Unfortunately, the COX-2 inhibitors in 2001–2010 failed to be adopted because of cardiovascular side effects [45]. Some authors described the development of acute myocardial infarction and sudden cardiac death, and in 2004 rofecoxib was withdrawn from the market. However, some additional studies show that inhibitors to isoenzyme COX-2 are powerful agents for control of intractable pain. They also have antitumor effects and are suitable for treatment of patients with bone metastasis what is due to inhibition of the production of cytokine and prostaglandin responsible for solid tumors and bone pain [46].

*4.1.3 Recommended non-conventional non-steroidal anti-inflammatory drugs*

chronic pain, alone or in combination, including cancer pain:

suppositories, and injections for IM use [47].

They are used in palliative medicine for the treatment of moderate and severe

It has analgesic, antipyretic, spasmolytic, and fewer anti-inflammatory effects. The possibility to provoke a life-threatening agranulocytosis after long use made metamizole for a long time to be under scrutiny. It was restricted in many countries in the world, but today after relevant clinical studies, the evidence has changed. Now, metamizole is recommended as an effective pain reliever in treatment of acute pain, particularly for renal colic and acute pancreatitis. It is found in form of tablets,

*Ketorolac* is the most widely used non-steroidal, anti-inflammatory drug for treatment of moderate to severe pain in adults. Its mode of action is by blocking both cyklooxygenase (COX1 and COX2) and decreasing the prostaglandin production. Its' medical use dates to 1989, predominantly for postoperative pain relief. It is found in form of tablets, nose spray, injection for IM and IV use, as well as eye drops. Its use shows many benefits. It is an efficient analgesic, an opioid sparing NSAID drug, and improves the bowel motility what makes it suitable for postoperative analgesia in abdominal and obstetric surgery. Its adverse effects limit its use up

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

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 cor-

*Metamizole* or dipyrone is an old non-opioid drug patented in 1922 in Germany.

*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*

**Acetaminophen** (paracetamol) chemically belongs to para-aminophenol derivatives; it is an active metabolite of phenacetin with an analgesic-antipyretic property and weak anti-inflammatory activity. It is recommended as a first step analgesic for mild to moderate pain [39]. Its mechanism of action is based to inhibition of central prostaglandin synthesis in the central nervous system and possible increases of noradrenaline in CNS and peripheral beta-endorphins [40]. It describes its analgesic and antipyretic activity without any effects on inflammation. Its use in PC is crucial on its formulations in form of tablets, coated tablets, or ampoules; therefore, it can be administered orally or IV. The onset of action for oral form is slow (15 min), so the use of intravenous application is the more appropriate. The maximum recommended therapeutic dose is 4000 mg/24 h, or 80/kg BW/24 h. According to a Meta analyses made from Schüchen RH et al. (2018), it was shown that there was no conclusive evidence that Acetaminophen in treatment of cancer pain produces satisfactory pain relief [41], but often it is used in combinations with opioids and it shows a decrease of the need for opioids (spearing effect). Its metabolites contribute to the toxic effects, so doses over its maximum dosage provoke liver damage. Therefore, it must be used with precaution in patients with liver diseases. **Aspirin** (acetylsalicylic acid) chemically belongs to the group of salicylates [42]. It is the most widely used drug for the treatment of mild to moderate pain. Aspirin has an analgesic-antipyretic, anti-inflammatory effect and prevents clotting. It is usually used for pain relief with low intensity. Its mode of action is through the decreased production of prostaglandins and thromboxane A2 by an irreversible inactivation of the ciclooxygenase enzymes (COX). It is an important additional medicine for patients with severe inflammatory pain (rheumatoid arthritis and similar). It is suitable for long-term use, because it is safe, with lower toxicity than paracetamol or opioids. In PC it can be safety used for pain control of acute pain, such as headache, toothache, minor back pain, for prophylaxis of myocardial infarction due to its well-established anti-platelet action. Its formulation is prepared in tablets and suppositories (100 mg, 300 mg, and 500 mg). Its use is 4–6 times per day, with maximum dose of 3000 mg/24 h. Among its side effects, the most important are appearance of peptic ulcer, allergy to salicylates and development of Reye's syndrome, if it is used in children younger than 16 years old. Overdosed, aspirin can cause cardiovascular instability, exacerbate underlying renal insufficiency, and even lead to coma with renal failure, metabolic acidosis, and respiratory arrest [42].

*4.1.1 Anti-inflammatory drugs*

*4.1.2 Non-steroidal anti-inflammatory drugs*

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of potent analgesics, antipyretics, and anti-inflammatory agents which are efficient in reliving of moderate to severe pain from musculoskeletal origin. They are widely in use at the institutions of palliative care as mono or combined therapy. The list of NSAID medicines is long and, in this document, only the most often used drugs will be mentioned. The NSAIDs mode of action is through peripheral and central inhibition of prostaglandin production from arachidonic acid through acetylating of two cyklooxygenase isoenzymes (COX-1 and/or COX-2). The nonselective NSAIDs inhibit the activity of both cyklooxygenase - COX-1 and COX-2. The most often used non-selective NSAIDs are ibuprofen, ketonal, diclophenac,

On the other side, the selective inhibitors to isoenzyme COX-2 (celecoxib, valdecoxib and rofecoxib) have the same analgesic effects as the non-selective NSAIDs,

**228**

naproxen, etc. [43].

but with a reduced risk for gastrointestinal tract (GIT) and platelets that makes those acceptable for pain management [44]. Unfortunately, the COX-2 inhibitors in 2001–2010 failed to be adopted because of cardiovascular side effects [45]. Some authors described the development of acute myocardial infarction and sudden cardiac death, and in 2004 rofecoxib was withdrawn from the market. However, some additional studies show that inhibitors to isoenzyme COX-2 are powerful agents for control of intractable pain. They also have antitumor effects and are suitable for treatment of patients with bone metastasis what is due to inhibition of the production of cytokine and prostaglandin responsible for solid tumors and bone pain [46].
