**3. Analgesic drug combinations**

The pharmacological therapeutic approach of multimodal analgesia includes all the frontline drugs available, used alone or in combination according to the specific needs of the patient [19].

Drugs for pain control fall into four main categories [20]:


The choice of the most appropriate drug combination should consider the pathogenic mechanisms of pain and satisfy the following criteria:



**207**

*Multimodal Pharmacological Analgesia in Pain Management*

anti-inflammatory activity [21].

**types of pain**

**4.1 Musculoskeletal pain (MP)**

Different drugs with different mechanism(s) of action may be combined for enhanced efficacy [20]. Analgesics relieve pain through a variety of mechanisms of

Analgesic combinations are currently recommended by several guidelines and are used in clinical practice [21]. In patients with moderate-to-severe pain, the general recommendation is the combination of opioid and non-opioid analgesics [22]:

1.Among the possible combinations, paracetamol has been associated with weak (e.g., codeine or tramadol) or strong (e.g., morphine or oxycodone) opioids. Besides being less effective than NSAIDs [23, 24], paracetamol may cause gastrointestinal (GI), cardiovascular (CV), and hepatic adverse effects [25, 26].

2.NSAID/opioid combinations have the advantage of anti-inflammatory and additive analgesic effect, along with a well-demonstrated opioid-sparing

• Hydrocodone/ibuprofen (7.5/400 mg) and oxycodone/ibuprofen (5/400 mg) are two oral, fixed-dose combination formulations, approved for the shortterm management of acute, moderate-to-severe pain. A single tablet provided better analgesia than low-dose hydrocodone/oxycodone or ibuprofen administered alone, in most trials, and appeared to be more effective than a single dose of some other fixed-dose combination analgesics [28–31].

• An FDC of the fast-acting NSAID, dexketoprofen trometamol, and the long-acting opioid, tramadol hydrochloride, have been recently developed to generate multimodal analgesia at lower and better tolerated doses than those of the single agents used alone. The different modes and sites of action of the two components, together with their complementary pharmacokinetic profiles, and the lower incidence of the typical side effects of each class [32–35] provides physicians with an effective and safe analgesic for the treatment of moderate-to-severe acute pain [36]. This FDC provides a comprehensive multimodal approach for moderate-to-severe acute pain, thanks to the central analgesic effect, peripheral analgesic action, and

activity [27]. Currently available NSAID/opioid FDCs include:

**4. Multimodal analgesia: different combinations for different** 

multimodal therapy to different pain conditions are the following.

cokinetic synergy and improved patient adherence.

Thanks to the possibility to minimize drug dosages optimizing efficacy, multimodal therapy is useful in various medical field, from acute pain management to post-trauma or postsurgical pain treatment, besides control of chronic pain and its exacerbations or reduction of pain associated with post-immobilization rehabilitation [19]. Each type of pain requires a specific analgesic therapy, which should also be personalized according to the patient's profile. The main applications of

Given the multiplicity of mechanisms responsible for MP, the combination of analgesics with different mechanisms of action for the relief of acute and chronic skeletal muscle pain is often recommended, with the possible advantage of pharma-

action along multiple sites of the nociceptive pathway (**Table 1**) [3].

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

#### **Table 1.**

*Mechanism of action of different analgesics (elaborated from text in Ref. [3]).*

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

*Pain Management - Practices, Novel Therapies and Bioactives*

Drugs for pain control fall into four main categories [20]:

3.opioids (morphine, hydromorphone, and oxycodone)

pathogenic mechanisms of pain and satisfy the following criteria:

colchicine, neurotrophine, and biologic drugs)

preferably act at different sites;

comorbidities of the patient; and

**Drug Mechanism of action**

Opioids Have multiple sites of action:

to therapy.

NMDA-receptor antagonists (ketamine)

Alpha-2 adrenergic

agonists

2.NSAIDs (ibuprofen, diclofenac, ketoprofen, and dexketoprofen)

4. adjuvant drugs (antidepressant, antiepileptic medications, corticosteroids,

The choice of the most appropriate drug combination should consider the

• The drugs to be combined should have different mechanisms of action and

• FDCs should be preferred, if available, aiming at improving patient adherence

NSAIDs Inhibit prostaglandin production by blocking cyclooxygenase both peripherally

Anticonvulsants Inhibit high-frequency neuronal firing by blocking sodium channels and reducing

spinal cord, where it activates primary afferent neurons.

Antidepressants Alter neurotransmitters that affect pain pathways by inhibiting presynaptic

pathway, resulting in improved inhibition of pain.

○ In the brain, they activate descending pain inhibitors. ○ In the periphery, they work by reducing inflammation.

○ In the spine, they decrease presynaptic calcium and sodium influx, production and release of excitatory amino acids, such as substance P, and

Bind to the NMDA receptor, thereby inhibiting glutamate activation. Glutamate is an excitatory amino acid found in laminae I, II, and III of the dorsal horn of the

Act on the descending pain pathways supra-spinally, activating receptors to stimulate acetylcholine release, and on the ascending pain pathways, by inhibiting substance P release from the primary afferent neurons, thus reducing

neuronal reuptake of serotonin and norepinephrine at the descending pain

• The drugs to be combined should not interfere with the preexisting

Paracetamol Inhibits prostaglandin synthesis in the central nervous system.

postsynaptic excitability.

neuron hyperexcitability.

transmission of pain.

*Mechanism of action of different analgesics (elaborated from text in Ref. [3]).*

and centrally.

1.weak analgesics (paracetamol and metamizole)

The pharmacological therapeutic approach of multimodal analgesia includes all the frontline drugs available, used alone or in combination according to the specific

**3. Analgesic drug combinations**

needs of the patient [19].

**206**

**Table 1.**

Different drugs with different mechanism(s) of action may be combined for enhanced efficacy [20]. Analgesics relieve pain through a variety of mechanisms of action along multiple sites of the nociceptive pathway (**Table 1**) [3].

Analgesic combinations are currently recommended by several guidelines and are used in clinical practice [21]. In patients with moderate-to-severe pain, the general recommendation is the combination of opioid and non-opioid analgesics [22]:

	- Hydrocodone/ibuprofen (7.5/400 mg) and oxycodone/ibuprofen (5/400 mg) are two oral, fixed-dose combination formulations, approved for the shortterm management of acute, moderate-to-severe pain. A single tablet provided better analgesia than low-dose hydrocodone/oxycodone or ibuprofen administered alone, in most trials, and appeared to be more effective than a single dose of some other fixed-dose combination analgesics [28–31].
	- An FDC of the fast-acting NSAID, dexketoprofen trometamol, and the long-acting opioid, tramadol hydrochloride, have been recently developed to generate multimodal analgesia at lower and better tolerated doses than those of the single agents used alone. The different modes and sites of action of the two components, together with their complementary pharmacokinetic profiles, and the lower incidence of the typical side effects of each class [32–35] provides physicians with an effective and safe analgesic for the treatment of moderate-to-severe acute pain [36]. This FDC provides a comprehensive multimodal approach for moderate-to-severe acute pain, thanks to the central analgesic effect, peripheral analgesic action, and anti-inflammatory activity [21].
