**4.3 Adjuvant analgesics**

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

syndrome are also present with an inappropriate use of the drug.

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

for PC patients.

ance to the drugs [71].

pain without a danger for overdoses.

which is distressing for the patient and the family [77].

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

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

"*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.

The development of constipation, nausea and vomiting; delirium, hallucina-

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

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"

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

tions, 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 toler-

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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, corticosteroids, NMDA receptor antagonists and others [78].

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 effectiveness as amitriptyline [81].

*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 bone marrow: suppression is possible to develop.

*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 present as side effects.

*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, bone fractures, osteoporosis with past fracture, etc.

*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.

It is used for treatment of severe acute and chronic pain. Its mechanism of action is complex but acts mainly as an antagonist of the NMDA receptor.

Ketamine is given through IV, IM, SC, oral, rectal, nasal, transdermal, epidural, and intrathecal way. It is a safe drug, without effects on respiration at analgesic doses, and less nausea and vomiting compared to opioids [85]. It is used with success in treatment of postoperative pain, refractory neuropathic pain syndromes, and severe Hyperalgesia as well. Its use in PC is controversial and is based on few un-homogeny studies and with a variety of obtained results. Recent study examining refractory cancer pain showed that ketamine used at moderate doses provides efficient analgesia [86].

*Canabis* still is with limited evidence of its use. The recent controlled trials and studies are unable to answer to the questions about its analgesic efficacy [87].

#### **5. Invasive analgesic techniques**

When the pain is refractory to pharmacological treatment, it is advised the use of *invasive analgesic techniques*. The use of local anesthetics provides a novel therapeutic approach in the treatment of pain. It is now established that neuraxial administration of drugs and use of neurolytic blocks are efficient in reduction of intractable cancer pain [88].

The analgesic effect of local anesthetics (procaine, bupivacaine, and lidocaine) is enabled by blocking the voltage sensitive Na+ channels, preventing the generation and conduction of nerve impulses. It has been also shown that chemical neuromodulation produces effective pain relief. For this purpose, intrathecally can be administered as local anesthetic, opioids, and adjuvant medications (alpha-adrenergic agonists, eg, clonidine), baclofen, and ziconotide. Baclofen is a GABA-B agonist who intrathecally inhibits both monosynaptic and postsynaptic reflexes at the spinal level producing muscle relaxation useful in some neuropathic pain syndromes [89]. Neuroaxial blocks as the epidural/intrathecal application of opioids (in low-dose) and non-opioids drugs (low concentration local anesthetic 0.125–0.25% levo-bupivacaine) increases the analgesic effects with few side effects [90].

Also, directly to the area of pain intrathecal pumps for small doses of medication can be used. The peripheral nerve blocks techniques, catheterization, and tumor infiltration prevent and reduce the bad memories of pain. The quality, duration, and safety of epidurally applied opioids have been intensively studied and compared [91]. It was suggested that sufentanil is a drug with the most promising profile [92]. Agents may be delivered via variety of catheters and ports. The implantation of a self-contained pump delivers medication at a specific rate into the subarachnoid space by a subcutaneously tunneled intrathecal catheter.

Neurolytic blocks or neurolysis of peripheral nerves or plexuses (celiac plexus or superior hypogastric plexus blocks), with phenol or alcohol, can be used for treatment of neoplasm pain, refractory to pharmacological treatment [93].

#### **6. Non-pharmacological therapy**

In recent years, due to the advancement of medical techniques and technology, other forms of treatment such as vertebroplasty, spinal cord stimulation, and prolo therapy are being used. The integration of the use of *interventional* medical and rehabilitative techniques improves the patients' lifestyle and helps reduce the pain. The use of surgical procedures is very rare for treatment of pain. There are some cases where surgery was used for relieving a nerve from compression, or at

**239**

*Multimodal Pain Management in the Setting of Palliative Care*

the disseminated metastatic cancer, a kyphoplasty was used at painful vertebral

In CONCLUSION, pain management is an especially important part of improving the quality of life in terminal patients. Because of the complexity of pain, the treatment must be multidisciplinary. Aggregation of PC with other settings, the use of MMA, could only permit better prevention of suffering at the end of the life. In the conclusion the next message will be greatly beneficial: undertreated or untreated pain at the end of the life may be cause patients' discomfort, stress, and suffering, which is a message to the clinicians to increase their awareness for pain control during the terminal phase of the life with a liberal

We would like to express our gratitude for the long collaboration with the ex- Director of the Hospice "Sue Rider"in Skopje, Dr. Mira Adzic, who helped us with experiencing and empathy with the real problems of patients in a palliative

We would like tank to Ms. Magdalena Mishkovska and the design studio

standard analgesic techniques also provide effective pain relief [95].

**The other** alternative forms of nonpharmacological therapy such as chiropractic therapy, acupuncture, music, movement therapies or yoga in integration with the

Transcutaneous electrical nerve stimulation (TENS) therapy involves the use of low-voltage electric currents to treat pain. This small device delivers the current at or near nerves producing electro-neuromodulation. It is widely used for treatment of intractable neuropathic and central pain but not for cancer pain and is

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

compression fractures [94].

advised in PC [96].

use of opioids and non-opioids.

**Acknowledgements**

care institution.

**Conflict of interest**

The authors declare no conflict of interest.

**Notes/thanks/other declarations**

"Magna –Scan" for their technical support.

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

the disseminated metastatic cancer, a kyphoplasty was used at painful vertebral compression fractures [94].

**The other** alternative forms of nonpharmacological therapy such as chiropractic therapy, acupuncture, music, movement therapies or yoga in integration with the standard analgesic techniques also provide effective pain relief [95].

Transcutaneous electrical nerve stimulation (TENS) therapy involves the use of low-voltage electric currents to treat pain. This small device delivers the current at or near nerves producing electro-neuromodulation. It is widely used for treatment of intractable neuropathic and central pain but not for cancer pain and is advised in PC [96].

In CONCLUSION, pain management is an especially important part of improving the quality of life in terminal patients. Because of the complexity of pain, the treatment must be multidisciplinary. Aggregation of PC with other settings, the use of MMA, could only permit better prevention of suffering at the end of the life. In the conclusion the next message will be greatly beneficial: undertreated or untreated pain at the end of the life may be cause patients' discomfort, stress, and suffering, which is a message to the clinicians to increase their awareness for pain control during the terminal phase of the life with a liberal use of opioids and non-opioids.
