**Abstract**

The knowledge of the pathophysiology of pain has gradually evolved in recent years, allowing the development of new management strategies, more specifically addressing single pain types and patient profiles. Despite these advancements, pain management still remains an open issue, given the limitations of single agent therapies, the potential abuse/misuse of opioids and the risk of adverse events. The advent of multimodal analgesic strategies paves the way for major improvements in pain management, combining increased efficacy with better tolerability and an opioid-sparing effect. The association of analgesics with different mechanisms of action represents a successful strategy for a wide range of pain conditions, minimizing side effects and taking advantage of the additive or synergistic actions of individual agents. Last but not least, the increasing availability of oral fixed-dose combinations of analgesics will offer further advantages over extemporaneous combinations, by increasing ease of administration and patient adherence to treatment.

**Keywords:** acute pain, chronic pain, analgesia, multimodal, drug combination, opioid, anti-inflammatory agents, nonsteroidal, acetaminophen

#### **1. Introduction**

Whatever its cause, pain, both acute and chronic, often emerges from multiple pathogenic pathways [1], which makes drug treatment particularly difficult [2]. In recent decades, the pharmacological arsenal against pain, in addition to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, has been enriched, on the one hand with molecules operating on different pain mechanisms (as anticonvulsants and antidepressants), and on the other hand with opioids [3]. However, the single-agent approach to pain remains quite challenging, since a single drug, acting on a single pain component, is generally not successful to achieve a clinically meaningful pain reduction, whereas its use at high doses may cause significant side effects [2]. On the other hand, the increasing prescription of opioids for noncancer chronic pain, besides providing limited clinical advantage compared with non-opioid alternatives [4], has opened the door to problematic opioid use and addiction problems: up to 50% of patients on long-term opioid therapy develop physical dependence or tolerance, leading to problematic opioid use in 5–10% of patients and to addiction in 1–2% [5]. As a consequence, pain management is far from being optimal and patients are exposed to the risks associated with misuse of single agents [6, 7].

Considering the complexity of pain pathogenesis, which involves multiple pathways [1], and the difficulty to reach complete symptoms control, especially for chronic pain which still affects 25–35% of adults in Europe [8], multimodal pharmacological analgesia may represent a possible solution to the still unsolved problem of pain management, thanks to a number of potential advantages: first, a decrease of the administered doses of the individual components; second, the reduction of side effects; and third, a simultaneous action on different pain components [9]. Thanks to these features, multimodal pharmacological therapy gives clinicians the opportunity to make a further step forward to a fully individualized therapy of pain in its various components and clinical manifestations [3].

In this chapter, we will present the therapeutic strategies currently available to address the specific needs in the treatment of different painful conditions and the new possibilities for pain intervention according to the multimodal approach.

#### **2. Pain management: unmet needs and future challenges**

Despite the multiple treatment options available, pain remains a mostly unresolved topic in every day clinical practice. The analgesic efficacy of single drug treatment is often not sufficient to provide an adequate pain relief, since most analgesic drugs cannot be prescribed at unlimited doses due to the ceiling effect and safety concerns. Another limitation of single-agent analgesia is that it cannot address the multiple pathways underlying pain pathogenesis. Combining drugs from different classes, with different and complementary mechanisms of action, may provide a better opportunity for effective analgesia at reduced doses of individual agents, with a potential reduction of dose-related adverse events.

Based on these considerations, clinical practice is gradually moving from a traditional one-fits-all approach to a more tailored strategy. The traditional approach to pain management refers to the three-step World Health Organization (WHO) pain ladder, which recommends the following regimen, based on the intensity of the patient's pain [10]:

Step I: a non-opioid analgesic should be used for moderate pain, with co-analgesics if necessary.

Step II: if pain persists or increases, a weak opioid may be added.

Step III: if pain still persists, then a change should be made to a strong opioid. By contrast, newer guidelines aim at treating pain according to the mechanism or mechanisms involved, i.e., neuropathic, nociceptive, or a combination of both [11]. Clinicians should seek to identify the basic pain mechanisms and treat the patient, accordingly, choosing the drug with the most appropriate mechanism of action [6].

Pain is a complex construct with sophisticated transmission pathways in the nervous system, which can be altered physiologically or pharmacologically [2]. Modulation of the transmission of pain can be divided into three approaches:


3.Modulating descending inhibitory pathways

Intervening in all three areas with multiple drugs is more effective than single drug treatment, and it allows to reduce the total dose of any one drug, thereby limiting unwanted effects [9].

**205**

improved adherence [18].

*Multimodal Pharmacological Analgesia in Pain Management*

*DOI: http://dx.doi.org/10.5772/intechopen.93620*

i.Peripherally acting drugs:

○ Local anesthetics

○ NSAIDS

○ Opiates

○ NSAIDS

○ Gabapentinoids

iii.Drugs acting centrally:

○ Opiates

○ Paracetamol

○ Tramadol

○ Clonidine

○ 5HT3 antagonists

tially additive or synergistic effects [12].

iv.Drugs acting on descending pathways:

Different drugs act at different areas:

ii.Drugs acting in the spinal cord:

○ N-methyl-D-aspartate (NMDA) receptor antagonists

The principle of multimedia analgesia is the use of a number of drugs (analgesic or adjuvant) in combination to achieve the best pain relief in acute or chronic pain. Combining analgesics that act by different mechanisms of action allows modulating multiple transmission pathways and enables individual agents to act with poten-

Multimodal analgesia is widely acknowledged to be superior to a single drug approach, having demonstrated improved pain relief, with the fewest side effects [2]. This concept was pharmacologically studied in the 1960s by Houde et al. [13], then clinically suggested (especially in postoperative pain) in the 1980s [14], and a few years later diffused by Kehlet and Dahl [9], who first introduced the term "multimodal" or "blended" analgesia. Since then, multimodal analgesia has been deeply studied, demonstrating a broader spectrum of action, greater efficacy, better patient compliance, and an improved efficacy/safety ratio compared with monotherapy [12]. As a result, analgesic combinations are recommended by the WHO, American Pain Society (APS), and American College of Rheumatology (ACR) [15–17] and are commonly used in clinical practice. As regards the ease of use, fixed-dose combinations (FDCs) may offer additional advantages, including ease of administration, reduction of pill burden, and

*Multimodal Pharmacological Analgesia in Pain Management DOI: http://dx.doi.org/10.5772/intechopen.93620*

Different drugs act at different areas:

### i.Peripherally acting drugs:


*Pain Management - Practices, Novel Therapies and Bioactives*

Considering the complexity of pain pathogenesis, which involves multiple pathways [1], and the difficulty to reach complete symptoms control, especially for chronic pain which still affects 25–35% of adults in Europe [8], multimodal pharmacological analgesia may represent a possible solution to the still unsolved problem of pain management, thanks to a number of potential advantages: first, a decrease of the administered doses of the individual components; second, the reduction of side effects; and third, a simultaneous action on different pain components [9]. Thanks to these features, multimodal pharmacological therapy gives clinicians the opportunity to make a further step forward to a fully individualized

therapy of pain in its various components and clinical manifestations [3].

**2. Pain management: unmet needs and future challenges**

vidual agents, with a potential reduction of dose-related adverse events.

Step II: if pain persists or increases, a weak opioid may be added.

1.Modulating the upward transmission

3.Modulating descending inhibitory pathways

2.Altering perception centrally

limiting unwanted effects [9].

In this chapter, we will present the therapeutic strategies currently available to address the specific needs in the treatment of different painful conditions and the new possibilities for pain intervention according to the multimodal approach.

Despite the multiple treatment options available, pain remains a mostly unresolved topic in every day clinical practice. The analgesic efficacy of single drug treatment is often not sufficient to provide an adequate pain relief, since most analgesic drugs cannot be prescribed at unlimited doses due to the ceiling effect and safety concerns. Another limitation of single-agent analgesia is that it cannot address the multiple pathways underlying pain pathogenesis. Combining drugs from different classes, with different and complementary mechanisms of action, may provide a better opportunity for effective analgesia at reduced doses of indi-

Based on these considerations, clinical practice is gradually moving from a traditional one-fits-all approach to a more tailored strategy. The traditional approach to pain management refers to the three-step World Health Organization (WHO) pain ladder, which recommends the following regimen, based on the intensity of the

Step I: a non-opioid analgesic should be used for moderate pain, with co-analgesics

Step III: if pain still persists, then a change should be made to a strong opioid. By contrast, newer guidelines aim at treating pain according to the mechanism or mechanisms involved, i.e., neuropathic, nociceptive, or a combination of both [11]. Clinicians should seek to identify the basic pain mechanisms and treat the patient, accordingly, choosing the drug with the most appropriate mechanism of action [6]. Pain is a complex construct with sophisticated transmission pathways in the nervous system, which can be altered physiologically or pharmacologically [2]. Modulation of the transmission of pain can be divided into three approaches:

Intervening in all three areas with multiple drugs is more effective than single drug treatment, and it allows to reduce the total dose of any one drug, thereby

**204**

patient's pain [10]:

if necessary.

	- Opiates
	- NSAIDS
	- N-methyl-D-aspartate (NMDA) receptor antagonists
	- Gabapentinoids
	- Opiates
	- Paracetamol
	- Tramadol
	- Clonidine
	- 5HT3 antagonists

The principle of multimedia analgesia is the use of a number of drugs (analgesic or adjuvant) in combination to achieve the best pain relief in acute or chronic pain. Combining analgesics that act by different mechanisms of action allows modulating multiple transmission pathways and enables individual agents to act with potentially additive or synergistic effects [12].

Multimodal analgesia is widely acknowledged to be superior to a single drug approach, having demonstrated improved pain relief, with the fewest side effects [2]. This concept was pharmacologically studied in the 1960s by Houde et al. [13], then clinically suggested (especially in postoperative pain) in the 1980s [14], and a few years later diffused by Kehlet and Dahl [9], who first introduced the term "multimodal" or "blended" analgesia. Since then, multimodal analgesia has been deeply studied, demonstrating a broader spectrum of action, greater efficacy, better patient compliance, and an improved efficacy/safety ratio compared with monotherapy [12]. As a result, analgesic combinations are recommended by the WHO, American Pain Society (APS), and American College of Rheumatology (ACR) [15–17] and are commonly used in clinical practice. As regards the ease of use, fixed-dose combinations (FDCs) may offer additional advantages, including ease of administration, reduction of pill burden, and improved adherence [18].
