Although paracetamol (acetaminophen) is one of the world’s most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. Today it is assumed that paracetamol has a pharmacological mechanism that interacts with a variety of physiological pathways, likely within the central nervous system [51]. Paracetamol as a single agent is an effective analgesic for mild to moderate acute pain. A single dose (1,000 mg of paracetamol) provides effective analgesia for about half of patients with acute postoperative pain, for a period of about 4 h, and is associated with few, mainly mild, adverse events [52]. Paracetamol is also useful in the treatment of moderate to severe pain when combined with other analgesics. Nonselective NSAIDs (non-steroidal anti-inflammatory drugs) given in addition to paracetamol improve analgesia compared to paracetamol alone [53, 54]. Paracetamol is also an effective adjunct to opioid analgesia, opioid requirements being reduced by 20 –30% when combined with a regular regimen of oral or rectal paracetamol [54]. The use of oral paracetamol in higher daily doses (1 g every 4 h) in addition to PCA morphine lowered pain scores, shortened the duration of PCA use, and improved patient satisfaction [55]. Paracetamol has fewer side effects than NSAIDs and can be used when the latter are contraindicated (e.g., patients with a history of asthma or peptic ulcers). It is commonly recommended that paracetamol should be used with caution or in reduced doses in patients with active liver disease, history of heavy alcohol intake, and glucose-6-phosphate dehydrogenase deficiency.

The term NSAIDs is used to refer to both nonselective NSAIDs and coxibs (COX-2 selective inhibitors). NSAIDs have a spectrum of analgesic, anti-inflammatory, and antipyretic effects and are effective analgesics in a variety of acute pain states. All NSAIDs primarily target the synthesis of prostaglandins and are known to be involved in numerous physiological systems such as the regulation of vascular tone, platelet aggregation, protective effects on the gastric mucosa, and regulation of the inflammatory cascade and renal perfusion. Cyclooxygenase (COX) is the enzyme responsible for the synthesis of prostaglandins, thromboxane, and leukotrienes by conversion of arachidonic acid. Cyclooxygenase is known to be present in at least two isomeric forms (COX-1 and COX-2) with different physiological effects. COX-1 is a constitutive enzyme (i.e., “daily household”) and is involved in the production of “physiological” prostaglandins. COX-2 is classically described as inducible and is expressed in inflamed/traumatized tissues but is lacking in others (e.g., platelets) [56].

Single doses of nonselective NSAIDs are effective in the treatment of moderate to severe pain after surgery, renal colic [57], and primary dysmenorrhea. Nonselective NSAIDs are integral components of multimodal and preventive analgesia [58]. However, while useful analgesic adjuncts, they are inadequate as the sole analgesic agent in the treatment of severe postoperative pain. When given in combination with opioids after surgery, nonselective NSAIDs resulted in better analgesia, reduced opioid consumption, and a lower incidence of postoperative nausea and vomiting (PONV) and sedation [59]. There was no effect on pruritus, urinary retention, and respiratory depression [60]. The combination of nonselective NSAIDs and paracetamol is effective [53]. Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone [61]. Coxibs are as effective as nonselective NSAIDs in the management of postoperative pain [62]. Preoperative coxibs reduced postoperative pain and opioid consumption and increased patient satisfaction [63].

Opioids are the mainstay of systemic analgesia for the treatment of moderate to severe acute pain. They form an essential part of a multimodal analgesia regimen. Although several new synthetic strong opioids have emerged in the past century, morphine is still the most widely used opioid throughout the world. The key principle for safe and effective use is to titrate the dose against pain relief and to minimize unwanted side effects [70]. Opioids can be administered orally, intravenously, subcutaneously, transdermally, epidurally, intrathecally, and intramuscularly. The intramuscular route however has lost favor and is less commonly used due to the ready availability of intravenous (IV) medications and the unnecessary pain and erratic absorption associated with this specific delivery method [71, 72]. Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient-controlled analgesia: PCA). PCA is an efficacious alternative to conventional systemic analgesia for postoperative pain control. PCA provides better pain control and greater patient satisfaction than conventional parenteral “as-needed” analgesia. Patients using PCA consumed higher amounts of opioids than the controls and had a higher incidence of pruritus (itching) but had a similar incidence of other adverse effects. Most experience exists with the use of morphine though all full opioid agonists given in appropriate doses produce the same analgesic effect and therapeutic index. Several opioids can be used in patient-controlled analgesia (Table 14.3).

In the periphery, after an event that causes direct nerve damage, a pronounced local inflammatory response ensues. Around the site of injury nocisponsive primary afferent neurons (PAF), damaged tissue, infiltration of inflammatory cells (mast cells, macrophages, and other immunocompetent cells), the vasculature, and sympathetic terminals result in the release of an inflammatory “soup.” Upon PAF injury, the density and function of ion channels alter, responsible for abnormal patterns of electric impulses and afferent input to the dorsal horn. Non-synaptic interactions between neurons (neurons modifying activity in adjacent neurons) occur in the dorsal root ganglia and increase the already existing neuronal hyperexcitability. Additionally, following nerve damage, a phenotypic switch of Aβ-fibers may contribute to abnormal, pronociceptive actions following innocuous stimulation [101, 102].

After peripheral nerve injury, these nerve endings may sprout with formation of neuromas (ectopic firing occurring both spontaneously and in response to stimulation) [103]. In neuropathic pain, there may also be an involvement of the sympathetic nervous system (sympathetic-induced pain) [104].

Under normal circumstances, a painful stimulus results in the release of excitatory amino acids (EAA) (glutamate, aspartate), neurotrophins, and peptides (such as substance P, neurokinin A, and calcitonin gene-related peptide, CGRP) from the central terminals of nociceptive Aδ- and C-fibers in the dorsal horn. The EAAs (especially glutamate) interact with receptor subtypes (presynaptically and postsynaptic second-order neurons) including ionotropic receptors such as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and NMDA (N-methyl-D-aspartate) [102, 105]. Intensive or persistent noxious stimulation (repeated stimulation) by glutamate augment activation of the NMDA receptor (key for longer-lasting increased excitability of dorsal horn neurons) and produces central sensitization. As a result, subthreshold noxious input can activate postsynaptic second-order neurons. Central sensitization manifests as an exaggerated or amplified response to noxious stimuli (hyperalgesia), a spread of pain sensitivity beyond the site of injury (secondary hyperalgesia), and as a reduced threshold for elicitating pain. Furthermore, C-fiber input initiates a progressive increase in excitability during the course of the stimulus (windup of action potential discharge) [106]. Once this windup phenomenon is initiated, blockade of peripheral nociceptive input may not completely stop dorsal horn neurons from firing [5]. In response to peripheral nerve injury, Aβ-fibers (normally mediating sensations of vibration and touch but not pain) sprout into superficial layers of the dorsal horn to make inappropriate contacts with nociponsive neurons together with an escape from inhibitory interneurons and descending pathways. This rewiring may lead to the perception of an innocuous stimulation as noxious. Hence, low-threshold mechanical stimuli (light brushing of the skin) activating Aβ-fibers may now cause neuronal hyperexcitability resulting in pain (mechanical allodynia) [107]. After peripheral nerve injury microglia, oligodendrocytes, and astrocytes (central nervous system glial cells) in the dorsal horn are activated and release proinflammatory mediators that modulate pain processing by affecting either presynaptic release of neurotransmitters and/or postsynaptic excitability. Activated glia increase the release of nociceptive neurotransmitters and increase the excitability of nociceptive second-order neurons creating widespread pain changes in the spinal cord. Emphasizing the possible role of these cells could lead to new therapeutic strategies in the management of intractable neuropathic pain [108].

If the train of noxious stimuli persists, changes occur in gene regulation (induction of new proteins and effects on the levels of expression of existing proteins including dynorphin and substance P) in central neurons providing larger and longer-lasting modifications in dorsal horn and primary afferent neurons. These, possible irreversible, processes of transcription-dependent central sensitization may induce permanent phenotypic/morphological changes responsible for the persistent (and partially independent of peripheral noxious input) pain in patients [109, 110].

The NMDA receptor is responsible for both the induction, the initiation of hyperalgesia, and the subsequent maintenance of neuropathic pain. Although excitatory events have been long considered as the key event in neuropathic pain, loss of spinal inhibitory control (diminished release of inhibitory gamma-aminobutyric-acid: GABA) upon PAF input into the dorsal horn amplifies processes elicitating neuronal hyperexcitability. Another major inhibitory system, next to the GABAergic system, related to pain is opioid-receptor-mediated analgesia. In neuropathic pain, however, NMDA receptor activation increases excitation in the pain-transmitting systems. Thus, more opioids will be required for analgesia. Reducing excitations (NMDA antagonism) while increasing inhibition (opioids) may control neuropathic pain [106].

Anatomic structures, including the periaqueductal gray area (PAG), the locus coeruleus, the nucleus raphe magnus, and several nuclei of the bulbar reticular formation give rise to descending modulatory pathways. These pathways may dampen or enhance the pain signal. The noradrenergic pathways, arising from the locus coeruleus play an antinociceptive role through activation of inhibitory dorsal horn localized α2-adrenorecepotors in inflammatory pain. The projections from the nucleus raphe magnus to the spinal cord are the major source of serotonin in the spinal cord. Although stimulation of the nucleus raphe magnus was shown to be antinociceptive in behavioral experiments, there is growing evidence that descending serotonergic pathways mediate both inhibition and enhancement of nociceptive processing in the dorsal horn [111]. The transmission of a pain signal from the periphery to the dorsal horn and supraspinal centers is a complex cascade of events. Although the transition from acute to chronic pain likely involves around activation of the NMDA receptor complex, phenotypic switches, structural reorganization in the dorsal horn, and loss of inhibitory circuits seem to underlie the most severe tractable form of neuropathic pain. Identification of molecular mechanisms of nociceptive signaling in the primary afferent neuron, the second-order neuron (dorsal horn), or beyond will provide a rational approach to neuropathic pain treatment and the selection of new targets for novel analgesic drug design [5].