Abstract
Tramadol—an atypical opioid analgesic—has a unique pharmacokinetic and pharmacodynamic profile, with opioidergic, noradrenergic, and serotonergic actions. Tramadol has long been used as a well-tolerated alternative to other drugs in moderate pain because of its opioidergic and monoaminergic activities. However, cumulative evidence has been gathered over the last few years that supports other likely mechanisms and uses of tramadol in pain management. Tramadol has modulatory effects on several mediators involved in pain signaling, such as voltage-gated sodium ion channels, transient receptor potential V1 channels, glutamate receptors, α2-adrenoceptors, adenosine receptors, and mechanisms involving substance P, calcitonin gene-related peptide, prostaglandin E2, and proinflammatory cytokines. Tramadol also modifies the crosstalk between neuronal and non-neuronal cells in peripheral and central sites. Through these molecular effects, tramadol could modulate peripheral and central neuronal hyperexcitability. Given the broad spectrum of molecular targets, tramadol as a unimodal analgesic relieves a broad range of pain types, such as postoperative, low back, and neuropathic pain and that associated with labor, osteoarthritis, fibromyalgia, and cancer. Moreover, tramadol has anxiolytic, antidepressant, and anti-shivering activities that could improve pain management outcomes. The aim of this review was to address these issues in the context of maladaptive physiological and psychological processes that are associated with different pain types.
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Tramadol attenuates the hyperexcitability of nociceptive neurons in incisional, inflammatory, and neuropathic pain by interfering with peripheral and central sensitizing mediators. |
Tramadol has wide applicability in different pain conditions, including postoperative, labor, neuropathic, and low back pain. |
Tramadol has other applications in pain management aside from the analgesic and anti-hyperalgesic modalities, including antidepressant, anxiolytic and anti-shivering roles. |
1 Pain
1.1 Pain Burden
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [1]. Pain, in its physiologic form as acute pain, acts as a warning sign against potential tissue damage and as such has an adaptive defensive role to maintain the integrity of tissues and organs. However, pain encountered in clinical settings, especially persisting and chronic pain, is pathophysiological and deviates from this paradigm and contributes to patient morbidity and mortality [2, 3]. A great deal of attention has been paid to effective control of pain due to increased awareness of its consequences. The World Health Organization (WHO) global burden of disease report in 2015 indicated that the leading cause of disability worldwide is pain, and this has been the case since 1990 [4].
Unrelieved pain has adverse effects on different biological systems, such as endocrine, immunological, cardiovascular, gastrointestinal, urinary, and musculoskeletal systems. These effects collectively constitute the classic stress response [2]. Although stress response has an adaptive function to promote survival in case of tissue injury, its persistence increases patient morbidity and might lead to shock [2]. Pain also has a significant impact on quality of life, especially in patients with chronic pain. One of the most important consequences of unrelieved pain is the development of anxiety and depression as common comorbidities [5, 6]. This has resulted in the use of anxiolytics and antidepressants as adjuvants during pain management [7]. The economic costs of untreated pain, either as direct or indirect expenses, have also risen dramatically [8].
Despite the increased awareness of its consequences, pain is undertreated, and this includes acute pain [9], cancer pain [10], low back pain [11], neuropathic pain [12], and osteoarthritis pain [13]. It has been proposed that further understanding of pain signaling mechanisms and mediators, together with improved knowledge about the pharmacology of different analgesic agents would substantially enhance pain control in different patient populations [3].
1.2 Pain Neuroplasticity
Significant advances in understanding the pathophysiologic basis of different pain types have been realized over the past few decades. Perhaps the most significant of these is that pain, though signaled through neurons, is not a hard-wired process but rather a dynamic one with changes in activity and strength depending on many factors, such as genetic [14], epigenetic [15], and environmental features [16]. Among the most important pain-modulating factors are the stimulus intensity and duration, whereby intense long-term stimulus induces biochemical, transcriptional, and structural changes in different pain-processing stages i.e., activity-dependent plasticity [17]. Another important discovery suggests that pain is not mediated solely via neuronal cells but also via non-neuronal cells, i.e., macrophages and glial cells actively precipitate pathological pain [18]. These non-neuronal cells act peripherally and centrally in a synergistic way to modulate pain [19]. Thus, pain could be viewed as neuronal/neuronal cell interactions and non-neuronal/neuronal cell interactions.
Understanding the dynamic nature of pain helps to highlight the analgesic and anti-hyperalgesic mechanisms of tramadol. This is important given that pain management is moving from empirical symptom control to mechanism-based pharmacological approaches [3, 20].
1.3 Peripheral and Central Sensitization
The increased sensitivity to stimuli that occurs in the periphery after tissue injury is termed peripheral sensitization and manifests as primary hyperalgesia. This process involves the action of a group of chemical mediators, for example, protons, bradykinin, substance P (SP), prostaglandin E2 (PGE2), histamine, serotonin (5-HT), adenosine triphosphate (ATP), proinflammatory cytokines, neuropeptides, and nerve growth factor [21], that are known collectively as “peripheral sensitizing soup” [2]. These mediators can cause direct stimulation of nociceptors, generating nerve impulses, or can sensitize nociceptors, increasing their excitability by lowering their activation threshold. Primary targets of these mediators are ion channels, and these are affected either directly via ligand-gated ion channels or indirectly via changes in the level of secondary messengers and transcriptional and post-transcriptional changes [21]. For example, protons directly activate acid-sensitive ion channels and heat-sensitive transient receptor potential V1 (TRPV1) channels, ATP activates P2X receptors, and 5-HT activates 5-HT3 receptors. On the other hand, mediators such as PGE2, cytokines, SP, and nerve growth factor indirectly activate nociceptors via phosphorylation or increased ion channel expression. The intermediary molecules of this process are cyclic adenosine monophosphate (cAMP), calcium, protein kinase A, and protein kinase C [22].
Continued exposure to intense impulse activity from peripheral C fibers initiates a state termed central sensitization, manifesting as spinal neuron hyperexcitability [23]. This then persists beyond the initiating stimulus via transcriptional and structural changes in the spinal cord [24]. In central sensitization, dorsal horn neurons are spontaneously active, with increased discharge, expanded receptive field, and decreased descending inhibitory pathway [25]. Manifestations of central sensitization are secondary hyperalgesia (exaggerated response to suprathreshold stimuli of uninjured tissue produced by Aδ fibers), allodynia (response to subthreshold stimuli produced by Aβ fibers), referred pain (response from uninjured tissue), and persistent pain (prolonged response after transient stimulus) [25]. Although central sensitization needs peripheral sensitization to develop, once it is established, peripheral input plays little or no role in maintaining it. This development in understanding followed the finding that local anesthetics have little effect on central sensitization when administered peripherally [26]. Hence, the attenuation of peripheral nociceptive input would have only a limited impact on effective pain management [17].
Central sensitization depends on various neurotransmitters, pro-inflammatory mediators, and secondary messengers. These factors collectively constitute what could be characterized as “central sensitizing soup”. One of the key mediators of central sensitization is the action of glutamate on N-methyl-D-aspartate (NMDA) receptors [2]. Cyclooxygenase (COX)-2 and its product PGE2 also contribute to central sensitization [27]. Other important mediators include glial cell activation—with the subsequent release of nitric oxide (NO)—ATP, reactive oxygen species, and proinflammatory cytokines [28]. SP, dynorphin, and neurokinin A participate in central sensitization. These different mediators form positive feedback loops, i.e., every member stimulates the release of other mediators and consequently increases synaptic transmission strength. Attenuation of these molecular targets via NMDA antagonists, COX inhibitors, and glial inhibitors has proven efficacious in alleviating central sensitization [3, 17, 29].
All those changes culminate in the development of long-term potentiation (LTP) at central synapses, which represents a convergence point for different hyperalgesia-associated conditions [30, 31]. An interesting observation regarding central sensitization is its role in diverse pain states. Central sensitization plays an active role in post-injury hypersensitivity, various chronic pain conditions (rheumatoid arthritis, osteoarthritis, fibromyalgia, neuropathic pain, and headache), transition from acute to chronic pain, and opioid-induced hyperalgesia [17, 29, 32,33,34]. Central sensitization is suggested to be a common etiology of these different syndromes, which in turn indicates that targeting neuronal hyperexcitability would have efficacy in different pain types [17].
Collectively, these data demonstrate that peripheral and central sensitization could be represented as a gymnastic barbell, with peripheral and central components representing the ends of the barbell. Hence, effective alleviation of pain requires dual modulation at both sites (Fig. 1a).
a Tissue injury initiates peripheral and central sensitization through activating a plethora of mediators. Peripheral mediators include Nav, TRPV1 channels, cytokines, PGE2, bradykinin, adenosine, and serotonin. Central mediators comprise Glu, SP, cytokines, PGE2, CGRP, macrophage polarization, and glial activation. This sensitization places a heavy burden on patient life quality. b Tramadol administration results in inhibiting neuronal sensitization via interfering with several key mediators. Molecular targets of tramadol include Nav, TRPV1 channels, MOR, NET, SERT, NK-1, AMPA, NMDA, A1 receptors, PGE2, cytokines, CGRP release, and inhibiting macrophage polarization and activated glial cells. This in turn could alleviate pain burden. 5-HT serotonin, 5-HT3 ionotropic serotonin receptor 3, A1R adenosine receptor 1, AMPA amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, ATP adenosine triphosphate, B2 bradykinin receptor 2, CGRP calcitonin gene-related peptide, CLR calcitonin-like receptor, CytR cytokine receptor, EP prostaglandin E2 receptor, Glu glutamate, MOR μ-opioid receptor, Nav voltage-gated sodium ion channel, NE norepinephrine, NET norepinephrine transporter, NK-1 neurokinin-1 receptor, NMDA N-methyl-D-aspartate receptor, P2X adenosine triphosphate ionotropic receptor, PGE2 prostaglandin E2, RAMP1 receptor activity modifying protein 1, SERT serotonin transporter, SP substance P, TRPV1 transient receptor potential V1
2 Tramadol
2.1 Tramadol Pharmacology
Tramadol is a synthetic analog of morphine and codeine with a unique mechanism of action and pharmacological effects that differ from those of other opioid drugs. Table 1 summarizes pharmacokinetic data for tramadol following oral and parenteral administration [35,36,37,38]. The main pharmacological effect of tramadol is alleviation of pain. Traditionally, tramadol analgesia has been attributed to opioidergic and monoaminergic effects [35,36,37], but other potential mechanisms and mediators that contribute to tramadol analgesia have been identified over the past few years as discussed in Sects. 2.2 and 2.3. Tramadol also affects muscarinic (M1 and M3) [39, 40], nicotinic (α7) [41], and serotonergic (5-HT2C) receptors [42] and K+ (delayed rectifier) ion channels [43]. However, the contribution of these effects to tramadol analgesia remains unclear. Tramadol has demonstrated efficacy in different pain types, including incisional and neuropathic pain, both acute and chronic pain, and pain of moderate to severe intensity [35,36,37]. Tramadol is recommended as a suitable drug for step 2 of the WHO Analgesic Ladder [44]. This wide spectrum of tramadol efficacy was reflected in the 2016 US drug spending report, as tramadol was among the top 20 prescribed medications [45]. Despite this, tramadol is not listed in the WHO essential medicines report [46], albeit it is included in other national reports of essential medicines [38].
Tramadol has a favorable adverse effect profile and is well-tolerated, with the most frequent adverse effects being nausea (6.1%), dizziness (4.6%), drowsiness (2.4%), fatigue (2.3%), sweating (1.9%), vomiting (1.7%), and dry mouth (1.6%) [37]. Other less common adverse effects include diarrhea and cardiovascular complications (tachycardia and postural hypotension; 0.1–1%) [38]. Respiratory depression, convulsions, tremors, bradycardia, hallucinations, and anxiety are rare (0.01–0.1%) [38]. Tramadol was reported as having a minimal effect on respiration at the recommended dosage in different clinical settings, even childbirth. The respiratory-depressant effect of tramadol is less than that of morphine, nalbuphine, buprenorphine, oxycodone, and pethidine. Cases of tramadol-precipitated respiratory depression showed parenteral administration of supra-therapeutic doses of tramadol 1000 mg in respiratory-compromised patients. This advantage is likely to benefit patients with respiratory disease, children, those in labor, and day-surgery patients [35,36,37]. Similarly, tramadol exerts few hemodynamic effects [35,36,37]. Another advantage of tramadol is the qualitative and quantitative similarity of the adverse effect profile with short- and long-term administration. Hence, unlike morphine, tramadol has no cumulative adverse effects that manifest with repeated administration [35,36,37]. Tramadol is described as having a pro-convulsant effect, with an estimated seizure frequency of < 1% [47]. However, this incidence is no different from that associated with other analgesics.
Overdose of tramadol is associated with lethargy (30%), nausea (14%), tachycardia (13%), agitation (10%), seizures (8%), coma (5%), hypertension (5%), respiratory depression (2%), and serotonin syndrome [35,36,37]. Tramadol toxicity is not considered lethal [35,36,37] and is relatively safe compared with other classic opioid analgesics [38]. Tramadol intoxication frequently includes co-ingestion of other drugs or alcohol [38]. Treatment of tramadol overdose involves respiratory support, administration of an opioid antagonist, naloxone or nalmefene, and anticonvulsant drugs, e.g., benzodiazepines in case of seizures [48].
Regarding the potential for tramadol dependence, animal studies showed that tramadol might produce physical dependence with mild withdrawal symptoms, but this was not reported in all studies [49, 50]. Human studies reported the dependence potential was low compared with that of morphine [50]. This was attributed to the lower affinity of tramadol and its metabolite to the μ-opioid receptor (MOR). Tramadol abuse potential increases with chronic administration. Tramadol withdrawal symptoms are similar to those in classic opioid abstinence syndrome and include restlessness, agitation, anxiety, sweating, insomnia, hyperkinesia, tremor, paresthesias, and gastrointestinal symptoms [38].
Self-administration studies in animals showed low abuse potential compared with morphine [38, 50, 51]. Clinical studies reported reinforcing effects of tramadol, but these were mild with less abuse potential than morphine [38, 50, 52]. This was confirmed by an epidemiologic study that extended over 14 years in Germany [53], and a post-marketing surveillance study in the US reached a similar conclusion [54]. Tramadol abuse is greater in individuals with a history of substance abuse, with an increasing incidence in African and West Asian countries. A WHO expert committee on drug dependence noted that tramadol’s status as a controlled drug differed internationally [38]. A risk-benefit assessment report of tramadol use in acute and chronic pain endorsed tramadol use in those conditions except for severe cancer pain and during general anesthesia [55]. The WHO expert committee also stated that tramadol is a relatively safe drug with a dependence and abuse potential lower than that of morphine [38].
2.2 Tramadol: Old and New Molecular Targets
Interestingly, molecular targets of tramadol are integral parts of the development of peripheral and central sensitization. Hence, through these molecular effects, tramadol could modulate peripheral and central neuronal hyperexcitability (Fig. 1b). Table 2 lists all the receptors and sites of tramadol action.
2.2.1 Effects of Tramadol on Neuronal/Neuronal Cell Interactions
Tramadol binds with low affinity (6000-fold less than that of morphine) to MOR and weakly to κ- and δ-opioid receptors. Tramadol’s active metabolite (M1) contributes significantly to its analgesic effects. MOR produces analgesia at three levels: supraspinal, spinal, and peripheral. Supraspinal analgesia is mediated at the thalamus, midbrain periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM) [56]. Spinal action occurs through inhibition of the ascending pain pathway via closure of presynaptic Cav channels and activation of postsynaptic Kv channels, resulting in decreasing nociceptive transmitter release and postsynaptic neuronal inhibition, respectively, and activation of the descending modulatory pain pathway via neuronal disinhibition. Opioid receptors on sensory nerve endings mediate a peripheral analgesic role via decreased peripheral firing of nociceptive stimuli [35,36,37, 57, 58].
Tramadol inhibits the reuptake of norepinephrine (NE) and 5-HT [35,36,37]. This transporter-blocking activity was achieved at concentrations that activate opioid receptors [Ki = 2.1 µM; Ki = 0.78 µM for the norepinephrine transporter (NET) and Ki = 0.9 µM for the serotonin transporter (SERT)] [35, 36]. NE and 5-HT are involved in the modulation of pain via activation of descending pain inhibitory pathways from the PAG and pons to secondary neurons of the spinal cord [59]. Much evidence has accumulated in both animal and human studies that supports the dual synergistic nature of tramadol analgesia [35,36,37]. Administration of the opioid antagonist naloxone resulted in partial antagonism of tramadol analgesia. Similar results were obtained with the α2-adrenoceptor (α2AR) blocker yohimbine and the 5-HT2 antagonist ritanserin [35,36,37].
Voltage-gated sodium ion channels have a well-recognized effect in the transduction and transmission of pain impulses and generation of ectopic impulses. Tramadol blocked NaV1.2 ion channels in vitro [60]. In vitro, tramadol’s blocking activity had similar kinetics to those of lidocaine with a higher affinity to fast inactivated sodium ion channels than to resting channels, and exhibited use-dependent blockade [60]. Hence, tramadol would not only suppress nerve conduction but also inhibits ectopic activities in sensitized neurons. This was confirmed in rat sciatic nerve preparations where tramadol and lidocaine produced the same conduction block with frequency dependence [61]. The membrane-stabilizing effect of tramadol was achieved at a higher concentration (half maximal inhibition (IC50) = 21 µM) than the typical plasma concentration of tramadol (1 µM) after a dose of 50 mg [60]. However, other in vivo studies reported that the local anesthetic concentration of tramadol did not significantly differ from that of established local anesthetics [62,63,64]. Other clinical studies that employed regional applications of tramadol supported its local anesthetic activity, for example, intradermal injection of tramadol produced loss of pain, touch, and temperature sensations [65]. Similar studies found that tramadol, like lidocaine and other local anesthetics, inhibited incisional pain and propofol injection pain [63, 66]. A possible explanation for this discrepancy is the sodium channel type involved. Peripheral sensory nerves harbor different types of sodium ion channels, such as Nav1.1, Nav1.7, Nav1.8, and Nav1.9. Tramadol could affect these types within its therapeutic range, but this remains to be investigated. Interestingly, the local anesthetic activity of tramadol was demonstrated in central synapses, where it produced central neural blockade after intrathecal injection in rats [67]. The local anesthetic activity of tramadol is not related to binding to MOR or inhibition of NET and SERT [68]. Tramadol analgesia was higher when administered locally rather than systematically, which might be attributed to higher local concentrations [69].
Tramadol also has actions at TRPV1 channels. In an in vitro study, tramadol activated the TRPV1 channel similarly to capsaicin, and its action was antagonized by capsazepine (TRPV1 receptor antagonist) [70]. This agonist activity was followed by tachyphylaxis. The action of tramadol on this channel could participate in its analgesic activity via desensitization of neurons in a similar manner to capsaicin. The half maximal effective concentration (EC50) of this effect was 0.08 ± 0.03 µM, which is within the systemic therapeutic range. In support of this notion, local administration of tramadol caused an initial burning sensation, pain, and erythema before the local anesthetic effect developed. Another in vitro study reported that tramadol did not affect this ion channel but rather blocked transient receptor potential ankyrin 1 (TRPA1) at concentrations of 0.1–10 µM. This ion channel is also expressed in sensory neurons with TRPV1 and is involved similarly in pain transmission and cold hyperalgesia [71]. This discrepancy was attributed to a difference in cell culture lines.
Tramadol and its active metabolite non-competitively blocked NMDA receptors in a dose-dependent manner in vitro [72]. Moreover, in vivo, tramadol blocked nociception induced by glutamate injection in the periphery [62]. Similarly, tramadol administered via intraperitoneal and intrathecal routes inhibited glutamate and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced biting behavior in experimental mice [73]. Another line of evidence comes from studies of tramadol as an antidepressant. Tramadol exerted antidepressant activity in the forced swimming test, which was attributed to NMDA-blocking activity [74]. Given the critical role of glutamate in nociception and neuroplastic changes in nociceptive transmission, it could be anticipated that tramadol might have a robust modulatory effect on this neuroplasticity.
Another potential mechanism of tramadol analgesia is blocking of the SP receptor, neurokinin-1 (NK1). The tramadol parent compound had little effect on NK1 expressed on Xenopus oocytes in vitro [75], but its active metabolite, O-demethyl tramadol, suppressed the receptor at clinically relevant concentrations [76]. In an in vivo study, tramadol blocked SP-induced biting behavior in mice [73]. SP is a primary neurotransmitter of afferent neurons of the ascending pain pathway; it is also involved in pain sensitization and cytokine release after tissue injury [77]. Several clinical trials have demonstrated the efficacy of tramadol in relieving osteoarthritis pain [78], activity that was attributed in one study to a significant reduction of synovial fluid concentrations of SP [79].
The role of calcitonin gene-related peptide (CGRP) is well-delineated in incisional, inflammatory, and neuropathic pain [80]. It has a dynamic role in the development and maintenance of peripheral and central sensitization to nociceptive stimuli [81]. In vitro, tramadol and tapentadol inhibited CGRP release centrally via serotonergic mechanisms mediated via 5-HT3 receptors [82]. This effect was achieved at clinically relevant tramadol concentrations (0.001–100 µM) [82].
Recently, tramadol’s antinociceptive action was shown to be mediated via adenosine A1 receptors in vivo [83]. Adenosine A1 receptors are located along the ascending pain pathway from peripheral to spinal to supraspinal sites and exert analgesic activity along this pathway [84]. Tramadol demonstrated analgesic activity in a formalin pain model when administered systemically and peripherally. This activity was reversed by administration of caffeine (non-selective adenosine receptor antagonist) and DPCPX (selective A1 receptor antagonist). Peripheral and spinal A1 receptors contributed to this analgesic activity [83]. Peripheral A1 receptors produce a decrease in the signaling of cAMP, protein kinase A, and NO/cyclic guanosine monophosphate (cGMP)/protein kinase G. Spinal actions of A1 receptors include pre- and post-synaptic inhibition of spinal neurons, decreased glutamate and neuropeptide release from primary afferent neurons, increased NE release from descending neurons, and decreased microglial activation. Supraspinal mechanisms are increased Kv channel conductance with hyperpolarization and decreased γ-amino-hydroxy butyric acid (GABA) transmission in the PAG. The wide array of adenosine actions explains its efficacy in inflammatory and neuropathic pain [84].
α2ARs located mainly in the spinal cord mediate the analgesic action of clonidine and other α2-agonists [85]. Spinal α2ARs regulate several mechanisms to inhibit nociceptive transmission, such as decreasing neurotransmitter release from first-order neurons through closing of Cav ion channels, hyperpolarizing dorsal horn neurons through opening Kv ion channels, inhibiting adenylate cyclase and thereby cAMP formation, and decreasing sympathetic outflow at the spinal cord level and the adrenal gland, given that NE plays an active role in sympathetically maintained pain [86]. Tramadol binding to α2AR was confirmed via radioligand-binding assay in vivo [87]. Similar findings were reported from studies of locus coeruleus (LC) activity, where in vitro and in vivo studies showed that tramadol attenuated LC activity indirectly through α2AR [88, 89]. This attenuation was not related to tramadol opioid activity but rather to increased extracellular NE concentrations secondary to inhibition of NET, similar to antidepressants [88, 89]. Tramadol’s effect on these receptors was achieved at clinically relevant concentrations (0.1–100 µM) [89]. Yohimbine (α2AR blocker) blocked the analgesic effects of tramadol [90].
2.2.2 Effects of Tramadol on Non-Neuronal/Neuronal Cell Interactions
In addition to effects on signaling between neurons, tramadol also has multiple effects on inflammatory mediators, signaling molecules, and cells. Various types of pain are associated with elevation of pro-inflammatory cytokine levels, and tramadol analgesia is associated with a decrease in these levels. For example, incisional pain in experimental rodents increased serum interleukin (IL)-6 and IL-2. Tramadol analgesia in these animals was associated with attenuation of the elevated cytokine levels [91]. Similarly, in osteoarthritis, tramadol decreased both the intensity of the joint pain and the rise in IL-6 levels [79]. In different preclinical pain models and clinical neuropathic pain (chronic constriction injury, spinal nerve ligation, herniated intervertebral disks, and carpal tunnel syndrome), tramadol diminished the elevations of pro-inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α and increased levels of the anti-inflammatory cytokines IL-10 [92,93,94,95].
PGE2 is a well-known mediator of peripheral and central hyperalgesia [96, 97]. Analgesia by COX inhibitors is attributed in part to inhibition of the formation of this key mediator [98, 99]. Tramadol anti-inflammatory effects in the carrageenan inflammation model were associated with a decrease in PGE2 levels in the inflammatory exudate [100]. Another study of inflammatory hyperalgesia using complete Freund’s adjuvant found that tramadol not only attenuated mechanical hyperalgesia but also decreased the elevation of PGE2 and TNF-α levels in the cerebrospinal fluid [101].
Another mediator of the tramadol anti-inflammatory effect is nuclear factor (NF)-κB. Evidence of the effects of tramadol on this crucial signaling mediator comes from a study of tramadol in a rodent model of myocardial infarction. In that study, tramadol not only attenuated the expression of NF-κB but also inhibited its activation [102]. Although this study was not focused on tramadol’s effect on pain, it does appear that inflammation plays a prominent role in both conditions. Similar results were reported in the formalin-inflammatory pain model [103]. NF-κB contributes to inflammatory hyperalgesia through upregulation of the COX-2 enzyme [104] and plays a significant role in glial activation following nerve injury [105]. This observation has been exploited by targeting this transcription factor to alleviate pathological pain [106]. Further studies are required to clarify the contribution of NF-κB to the actions of tramadol.
NO plays peripheral and central bi-modal roles in modulating pain transmission [107, 108]. NO has pro- and antinociceptive effects depending on a host of factors, including NO concentration, location, and the pathophysiological process [107]. Inflammatory pain includes induction of NO synthase (NOS) in the periphery, and a positive feedback loop between NO and cytokines has been observed. The central actions of this gaseous transmitter enhance pain signaling via different mechanisms—for example, glutamate signaling is mediated in large part via release of NO, whereas glutamate-induced secondary hyperalgesia is mediated via NO. NO also enhances the release of SP and CGRP via retrograde transmission [107]. Stimulation of the COX enzyme and production of hyperalgesic prostaglandins is driven by the release of NO. NOS inhibitors have proven efficacy in the alleviation of neuropathy-associated hyperalgesia. On the other hand, NO precursors such as sodium nitroprusside and nitrates induced peripheral analgesia in nociceptive tests [107]. Additionally, NO was reported to mediate the peripheral and central antinociceptive effects of different analgesics, including opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetylcholine [107]. This uncertainty extends to detecting the role of NO signaling in mediating tramadol analgesia. Thus, some studies found that tramadol produced its effect via activation of the NO–cGMP pathway, whereas NOS inhibitors reduced tramadol analgesia [109]. On the other hand, tramadol analgesia was increased by NOS inhibitors and reduced by NO precursors [110]. Given these contradictory observations, the contribution of NO signaling to tramadol analgesia remains to be determined.
Tramadol also modulates the activity of non-neuronal immune cells that operate in peripheral and central synapses. In one in vitro study, tramadol regulated the polarization of M1 and M2 macrophages by inhibiting cytokines secreted from M1 cells and enhancing the expression of Arg1, Mrc1, Ym1, and Fizz1 from M2 cells, which are known to combat inflammation [111]. Macrophage polarization is a well-known contributor to the development of peripheral inflammation and sensitization in different pain conditions, and shifting the polarization towards an M2 state could relieve neuropathic pain [112]. However, more studies are required to determine whether this effect indeed contributes to tramadol analgesia in vivo.
Regarding the effects of tramadol on central glial cells, several preclinical studies showed that tramadol inhibits the activation of these cells [94, 113, 114]. It could be assumed that tramadol’s inhibitory effect on glial cells could occur secondary to neuronal inhibition via MOR given the crosstalk between neuronal and glial cells. However, this assumption is erroneous since morphine, which is more potent than tramadol, has no reported inhibitory effect on glial cells. This confirms that tramadol inhibits glial activation directly and not by dampening neuronal activity [113].
2.3 Tramadol, Other Opioids, and Hyperalgesia
As discussed, peripheral and central sensitization are now widely accepted to be an integral part of every pain condition, from mild headache and fibromyalgia to the transition from acute to chronic pain [17, 34]. The search for drugs that can modify these processes and hence improve pain control is ongoing, but there is still a significant way to go to achieve this goal. For example, between 10 and 30% of surgical patients develop chronic postsurgical pain after one year postoperatively [115]. Moreover, some analgesic drugs such as morphine potentiate this neuronal sensitization rather than dampen it. Morphine, fentanyl, and other opioids are known to produce opioid-induced hyperalgesia during acute or chronic administration [116]. The manifestations and molecular mechanisms of opioid-induced hyperalgesia is similar to hyperalgesia encountered in different pain settings [117]. One important interaction exists between tissue injury and opioid administration: the so-called “two hit hypothesis”, where hyperalgesia develops after two hits occurring in any order, opioid administration and tissue injury [118]. Inflammation has been held responsible for this interaction, where both tissue injury and opioid administration have pro-inflammatory effects that cooperate to produce the observable effect [118]. For this reason, opioids such as morphine facilitate the transition from acute to chronic pain and can worsen some forms of chronic pain [118,119,120].
Studies that have tested the effects of tramadol on peripheral and central sensitization in terms of nerve electrical activity and synaptic potentiation are currently lacking. However, the anti-sensitizing effects of tramadol have been demonstrated in the three types of pain: incisional, inflammatory, and neuropathic. Remarkably, the efficacy of tramadol in those models has been associated with modulation of integral components in peripheral and central sensitization, such as glial activation, glutamatergic transmission, and cytokine and prostaglandin release. In a preclinical study of incisional pain, latent pain sensitization developed 21 days after incision (latent pain sensitization is responsible for chronic postsurgical pain), and a single administration of tramadol before the surgical insult inhibited this sensitization [121]. In that study, tramadol efficacy was attributed to inhibition of microglial activation. In a parallel study, tramadol reversed mechanical hyperalgesia that developed after incisional pain, with simultaneous reduction in elevated levels of IL-6 [91].
The development of central sensitization in a preclinical animal model of rheumatoid arthritis was linked to phosphorylation and increased expression of NMDA receptors [122]. In this study, a NMDA receptor antagonist reduced hyperalgesia. Interestingly, intrathecal administration of tramadol attenuated hyperalgesia and the expression and phosphorylation of NMDA receptors. In another study, complete Freund’s adjuvant-induced mechanical hyperalgesia was associated with elevations in PGE2 and TNF-α. Tramadol administration reversed this hyperalgesia with concurrent reduction in PGE2 level. Similarly, tramadol activity in animal behavioral tests could be used to infer its effects on sensitization phenomenon. Thermal and mechanical hyperalgesia to paw inflammation was suggested to be a valid model of sensitization [24, 123]. This model confirmed the activity of different anti-hyperalgesic agents, including NMDA receptor antagonists, COX inhibitors, and the antiepileptics [124,125,126]. Hence, tramadol efficacy in this model could be used as a predictor of its anti-hyperalgesic properties [127]. Systemic and local (in the hind paw of rats) administration of tramadol alleviated inflammation-associated hyperalgesia even at doses that did not affect basal nociceptive thresholds [127, 128].
Additional evidence for efficacy comes from the effects of tramadol on neuropathic pain. Neuropathic pain involves neuronal sensitization in its pathophysiology [129]. Several studies that established the efficacy of tramadol in neuropathic pain have related the efficacy to depressing glial activation and cytokine release [93, 95, 113, 114]. In one of those reports, efficacy was still demonstrable even after tramadol cessation for about 1 week. That study suggested that repeated tramadol administration induces long-term plastic changes in pain signaling pathways that persist after its withdrawal [113]. Glial cells have a critical time window for activation after encountering a painful stimulus, and the absence of glial cells via depletion has a long-term effect on pain hypersensitivity, even after glial repopulation [19]. Tramadol could similarly attenuate glial activation, and this effect would persist for extended periods. This extended analgesia was still demonstrable when tramadol analgesia blockers were used. It was suggested that pharmacological efficacy in neuropathic pain could be used as a likely predictor of neuronal sensitization modulation [130]. Given the efficacy of tramadol in attenuating neuropathic pain [131], this could be attributed in part to the ability of tramadol to alter sensitization.
Further evidence for tramadol’s anti-hyperalgesic efficacy comes from its local anesthetic activity. Tramadol exerts a membrane-stabilizing effect that is independent of its receptor profile [62,63,64, 68], and local anesthetic activity has been shown in peripheral and central synapses [67]. Intriguingly, peripheral and central administration of local anesthetics could normalize both arms of neuronal sensitization [132, 133]. Through neuronal blockade, lidocaine inhibited the development of chronic postsurgical pain [134]. Hence, by extrapolation, it could be anticipated that tramadol could exert a similar effect to local anesthetics. In support of this hypothesis, tramadol, when combined with an NSAID, inhibited transition from acute to chronic back pain when compared with NSAID alone [135]. Another study found that tramadol combined with diclofenac inhibited postoperative secondary hyperalgesia, which indicates attenuation of central sensitization [136]. For those reasons, the evidence for the anti-sensitizing effect of tramadol is strong and carries high translational value.
Two studies have reported conflicting findings, suggesting that tramadol exerts a hyperalgesic effect. One clinical report found that tramadol administration for 1 and 4 years in chronic pain produced hyperalgesia [137], whereas a preclinical study found that a single administration of tramadol in Wistar rats decreased the mechanical threshold in an absence-of-pain model [138]. The authors argued that tramadol’s affinity to the MOR with subsequent activation of counter-regulatory pathways (e.g., glutamate activation, pro-inflammatory cytokine release, and glial activation) was responsible for tramadol-induced hyperalgesia [139]. However, this assumption and those studies contain some limitations. The contribution of MOR to hyperalgesia is controversial and not yet established [139]. Tramadol use is not associated with the counter-regulatory pathways mentioned—in fact the opposite is true, and this has been confirmed in several studies. The Toll-like receptor (TLR) is an important mediator of opioid-induced hyperalgesia, and tramadol has no reported affinity with this receptor. The first record was a case report of two subjects and is subject to the limitations of this source of information. For those reasons, the current evidence for the pro-sensitizing effect of tramadol is weak.
Tramadol is recommended as an anti-sensitizing agent that could be used to combat central sensitization in chronic pain states [33, 140]. The authors based their argument on the dual opioidergic and monoaminergic activities of tramadol to produce this effect. However, this does not rule out other mechanisms that may operate in tramadol-induced de-sensitization. Given the involvement of neuronal sensitization in most forms of pain, tramadol anti-sensitizing effects could explain its broad spectrum of efficacy in different pain conditions.
2.4 Tramadol Broad-Spectrum Analgesia
Tramadol use as a unimodal agent in different pain conditions has been investigated in several preclinical and clinical studies. Systematic reviews and meta-analyses have shown fair evidence of tramadol efficacy in different pain conditions, such as postoperative [141], procedural [142], dental [141], migraine headache [143], abdominal [144,145,146,147], cancer [148, 149], neuropathic [131], fibromyalgia [150], arthritis [78], and back pain [151]. A systematic review has reported similar evidence of tramadol efficacy in chronic non-cancer pain [152]. Preclinical studies likewise support the broad efficacy of tramadol [153]. Table 3 provides representative examples of clinical pain conditions that explored tramadol analgesia. Given space constraints, the author confined tramadol studies in each pain category to three trials, with clinical studies preferred over preclinical when available. Table 3 shows that tramadol is a broad-spectrum analgesic agent despite the variance in dosage, power of each study, subjects, reference drug, and primary and secondary outcomes. Similar findings about tramadol’s spectrum of activity have been reported in other comprehensive reviews [35,36,37, 154, 155]. This broad-spectrum activity could be attributed in part to a tramadol synergistic interaction between opioidergic and monoaminergic activities. However, other mechanisms could also contribute.
An important fact about pain that should not be overlooked is that significant comorbidity exists, and patients can have multiple pain diagnoses [156]. For example, headache has been reported to be associated with other pain types [157]. Similar comorbidity has been found in pain related to cancer and multiple sclerosis [156] and in neuropathic and low back pain [158]. The occurrence of one pain type predisposes the affected individual to developing another pain type. This has been explained based on neuronal sensitization, whereby sensitized neurons have lower excitability thresholds, which prompt them to develop another pain [26]. This is reflected in prescription of more than one analgesic agent for each patient [156]. Multiple pain comorbidity is a huge clinical and economic challenge [156]. Theoretically, the broad-spectrum analgesia provided by tramadol could help in these conditions by replacing polypharmacy with a single agent with subsequent reduction in economic costs, patient noncompliance, and risk of drug interactions.
2.5 Other Applications of Tramadol in Pain Management
2.5.1 Combined Analgesia
One of the most widely employed strategies in the management of both acute and chronic pain is multimodal analgesia. The concept of multimodal analgesia implies the use of more than one method or modality to control pain with the target of enhancing the beneficial effects and reducing the adverse effects of the pain management. For example, combining NSAIDs or adjuvant analgesics with opioid drugs reduces opioid requirements, adverse effects, and the development of tolerance and dependence. Moreover, enhanced analgesia may be obtained through agents acting via different mechanisms [196,197,198]. Another reported advantage of multimodal analgesia is the possible reduction of acute pain transition to chronic pain [9].
In preclinical studies, tramadol potentiated the analgesic activities of several agents, such as acetaminophen [199], NSAIDs [200], morphine [201, 202], antidepressants [203], antiepileptics [204], local anesthetics [205], NMDA antagonists [206], α2AR agonists [207], and corticosteroids [208]. Systematic reviews and meta-analyses of clinical studies have shown similar results relating to tramadol’s synergistic interaction with other analgesics, such as acetaminophen [209] and morphine [210]. Fixed-dose combinations of tramadol have also reached the market in the form of tramadol + acetaminophen and tramadol + dexketoprofen [211, 212]. Other combinations are also in development, such as tramadol + celecoxib [213]. The analgesic spectrum of these combinations is wide, encompassing acute and chronic, incisional, inflammatory, and neuropathic pain states. This could be explained based on the wide variety of tramadol’s molecular actions, which boost the efficacy of other analgesics. For example, (1) tramadol combined with gabapentin showed synergistic suppression of elevated IL-1β [214]‚ and (2) tramadol prolonged lidocaine’s duration in intravenous regional anesthesia, an effect that was mediated via the nerve-blocking activity of tramadol [215].
Despite the established value of multimodal analgesia, this does not imply that combining more than one analgesic in any pain category would result in superior efficacy and reduced adverse effects. Several clinical trials denied this notion, for example, the combination of a cholecystokinin antagonist and an opioid [216]. Furthermore, combined analgesics could have increased toxicity, such as serotonin syndrome with a tramadol + serotonergic antidepressant combination [216]. In view of such concerns, tramadol combination regimens should be carefully designed and should be properly justified based on three factors: (1) specific mechanism of each combined drug, (2) adverse effects of combined drugs, and (3) pain category-specific targets [216]. Knowledge of the analgesic mechanism, uses, and adverse effects of different analgesic drugs would help to unveil and optimize the value of combining tramadol with these agents in different pain conditions.
2.5.2 Local Analgesia
Incisional, inflammatory, and neuropathic pain involves activation of primary afferent neurons, resulting in hyperexcitability. Targeting peripheral neuronal facilitation via topical administration has been shown to be effective in combating these three pain types. Furthermore, this route of administration has other merits, including achieving a high concentration of the drug at the injury site, reducing systemic toxicity, and reducing drug interaction risk [22]. Topical agents that have shown efficacy in the clinical setting include NSAIDs, local anesthetics, corticosteroids, and capsaicin [22].
Topical tramadol application improved tonsillectomy pain (swabs soaked with tramadol were applied to tonsillar fossa) [217, 218]. Similar findings were reported in dental pain (tramadol was applied to extraction sockets and on the submucosa) [219, 220] and postoperative sore throat (tramadol was applied using gargle) [221]. Intra-articular injection of tramadol provided adequate analgesia in arthroscopic knee surgery and an animal model of joint inflammation [222,223,224]. This efficacy could be attributed to two factors, local anesthetic action and attenuation of peripheral inflammatory reactions. Given the involvement of multiple mediators in the activation of peripheral nerves, simultaneous targeting of those mediators would be advantageous. Topical tramadol could effectively control different pain types through effects on a wide variety of mediators, such as neuronal conduction, inflammatory mediators, and macrophage polarization.
2.5.3 Comorbid Diseases with Pain
It is now widely accepted that pain, especially when pain is chronic, is associated with other diseases that also increase the pain burden on both individuals and society. These pain-associated comorbidities include depression, anxiety, sleep disturbances, and fatigue. The most important of them are depression and anxiety, where 60% of patients with chronic pain also have depression, and 33% have severe depression [225]. In another study, 70% of patients with chronic pain had anxiety [226]. Interestingly, the severity of anxiety and depression was correlated with pain intensity. For those reasons, anxiolytics and antidepressants have a role in pain management [227, 228].
Tramadol use in pain is associated with anxiolytic and antidepressant activities. For example, in a preclinical model of neuropathic pain with anxiety and depression, tramadol’s anti-hyperalgesic effect was associated with anxiolytic and antidepressant actions in elevated plus maze and forced swimming test [229]. In a clinical study of low back pain with depression, tramadol in combination with acetaminophen significantly improved pain and depression outcomes [230]. It has been suggested that the anxiolytic and antidepressant activities of tramadol occur secondary to alleviation of pain. However, preclinical studies in an animal model of depression with no pain have shown that tramadol indeed exerted antidepressant and anxiolytic actions independent of the presence or absence of pain stimuli [74, 231, 232]. Similarly, tramadol-independent effects on depression and anxiety have been reported in clinical settings [233, 234].
An emerging hypothesis of major depression has linked alterations in glutamate signaling and neuroplastic changes to the development of symptoms [235]. Ketamine, a NMDA receptor antagonist, has shown antidepressant activity in different preclinical and clinical studies [236]. Some studies have linked the antidepressant effect of tramadol to NMDA receptor antagonism [74, 231]. Another possible explanation for tramadol’s antidepressant activity comes from microdialysis studies, in which tramadol was found to affect monoaminergic transmission in the ventral hippocampus of freely moving rats in a similar way to duloxetine, venlafaxine, and clomipramine [237], and changes in monoamine levels initiate neuroplastic changes associated with antidepressant activity [238].
2.5.4 Postoperative Shivering
Shivering is a common postanesthetic complication that increases patient discomfort and pain intensity, besides having other metabolic effects. The pathophysiology of this process is poorly understood, but perioperative hypothermia remains the main culprit [239]. Treatment of postanesthetic shivering consists of pharmacological and non-pharmacological approaches. Clinical pharmacological treatment is mostly empirical. To date, meperidine has been the most validated approach [239]. Tramadol’s anti-shivering effects have been demonstrated in several clinical trials, and the efficacy of tramadol was comparable to that of meperidine [240, 241]. The mechanism behind tramadol’s efficacy is unclear but was attributed to blocking of NMDA receptors [242]. Moreover, the high safety profile and weak sedative effect of tramadol add more weight to its potential therapeutic value [243].
3 New Drugs in Development
Although tramadol and other approved analgesics have shown good results in different pain conditions, they have limited efficacy in different clinical conditions. Hence, considerable research effort is ongoing to develop novel analgesic drugs despite obstacles imposed by the complexity of pain pathways, clinical pain heterogeneity, and poor translational value of preclinical models [244]. Drug development of novel analgesics is moving towards a more targeted-therapy approach, which offers promising prospects regarding better control of pain [20, 245].
Current drug discovery approaches are directed towards three targets: opioid and non-opioid G-protein-coupled receptors (GPCRs), ion channels, and enzymes [244]. Drug classes targeting opioid GPCRs include abuse-deterrent opioids, peripherally restricted receptor ligands, bivalent ligands, and biased ligands. Non-opioid GPCRs include cannabinoid, angiotensin type 2, α2ARs, and chemokine receptors. Ion channel targets are TRPV1, Nav1.7, Nav1.8 sodium channels, Cav2.2, Cav3.2 channels, and Kv7 and K2P channels. Sepiapterin reductase, microsomal PGE2 synthase 1, soluble epoxide hydrolase, and proteases are of interest for clinical development [244].
4 Conclusion and Future Directions
Current evidence proposes that different components of nociceptive signaling, such as primary afferent neuronal activity, glutamate signaling, macrophages, glial cells, cytokines, and chemokine release, are polarized by tissue/nerve injury in such a way that these components support hyperalgesia and that tramadol could interrupt this polarization. Therefore, tramadol as a uni- or multimodal agent could enhance the outcome of patients with different pain conditions. Despite the body of information summarized in this review, much work remains to establish the anti-sensitizing effect of tramadol. For example, tramadol’s effect on other molecular mediators of pain and hyperalgesia, such as Nav1.7, Nav1.8, brain-derived neurotrophic factor, LTP development at central synapses, TLR signaling, and macrophage polarization, etc., should be thoroughly examined. Additionally, tramadol’s utility in multiple pain comorbidity should be investigated and compared with other polymodal regimens, with pain intensity, patient compliance, and overall cost as primary and secondary outcomes.
References
Merskey H. Pain terms: a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979;6:249–52.
Lamont LA, Tranquilli WJ, Grimm KA. Physiology of pain. Vet Clin Small Anim Pract. 2000;30(4):703–28.
Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441–51.
Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545.
Bair MJ, et al. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163(20):2433–45.
Greenberg J, Burns JW. Pain anxiety among chronic pain patients: specific phobia or manifestation of anxiety sensitivity? Behav Res Ther. 2003;41(2):223–40.
Jann MW, Slade JH. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy. 2007;27(11):1571–87.
Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13(8):715–24.
Sinatra R. Causes and consequences of inadequate management of acute pain. Pain Med. 2010;11(12):1859–71.
Deandrea S, et al. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol. 2008;19(12):1985–91.
Rizzardo A, et al. Low-back pain at the emergency department: still not being managed? Ther Clin Risk Manag. 2016;12:183.
Harden N, Cohen M. Unmet needs in the management of neuropathic pain. J Pain Symptom Manag. 2003;25(5):S12–7.
Conaghan PG, et al. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology. 2014;54(2):270–7.
Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances. J Med Genet. 2012;49(1):1–9.
Stephens KE, et al. Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery. Cytokine. 2017;99:203–13.
Malenbaum S, et al. Pain in its environmental context: implications for designing environments to enhance pain control. Pain. 2008;134(3):241.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3):S2–15.
Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16(11):1267.
Peng J, et al. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat Commun. 2016;7:12029.
Vardeh D, Mannion RJ, Woolf CJ. Toward a mechanism-based approach to pain diagnosis. J Pain. 2016;17(9):T50–69.
Rang H, Bevan S, Dray A. Chemical activation of nociceptive peripheral neurones. Br Med Bull. 1991;47(3):534–48.
Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev. 2003;55(1):1–20.
Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013;74(5):630–6.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.
Berry PH, et al. Pain: current understanding of assessment, management, and treatments. VA: National Pharmaceutical Council and the Joint Commission for the Accreditation of Healthcare Organizations; 2001.
Woolf CJ. Central sensitization uncovering the relation between pain and plasticity. Anesthesiology. 2007;106(4):864–7.
Seybold VS, Jia Y-P, Abrahams LG. Cyclo-oxygenase-2 contributes to central sensitization in rats with peripheral inflammation. Pain. 2003;105(1–2):47–55.
Ji R-R, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154:S10–28.
Arout CA, et al. Targeting opioid-induced hyperalgesia in clinical treatment: neurobiological considerations. CNS Drugs. 2015;29(6):465–86.
Sandkühler J. Understanding LTP in pain pathways. Mol Pain. 2007;3(1):9.
Sandkühler J, Gruber-Schoffnegger D. Hyperalgesia by synaptic long-term potentiation (LTP): an update. Curr Opin Pharmacol. 2012;12(1):18–27.
Voscopoulos C, Lema M. When does acute pain become chronic? Br J Anaesth. 2010;105:i69–85.
Nijs J, et al. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: an update. Expert Opin Pharmacother. 2014;15(12):1671–83.
Arendt-Nielsen L, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018;22(2):216–41.
Lee CR, McTavish D, Sorkin EM. Tramadol. Drugs. 1993;46(2):313–40.
Scott LJ, Perry CM. Tramadol. Drugs. 2000;60(1):139–76.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.
World Health Organization. WHO expert committee on drug dependence. Geneva: World Health Organization; 2018.
Shiraishi M, et al. Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther. 2001;299(1):255–60.
Shiga Y, et al. The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M3 receptors. Anesth Analg. 2002;95(5):1269–73.
Shiraishi M, et al. Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing α7 receptors. Br J Pharmacol. 2002;136(2):207–16.
Ogata J, et al. The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg. 2004;98(5):1401–6.
Tsai TY, et al. Tramadol-induced blockade of delayed rectifier potassium current in NG108-15 neuronal cells. Eur J Pain. 2006;10(7):597.
Tassinari D, et al. The second step of the analgesic ladder and oral tramadol in the treatment of mild to moderate cancer pain: a systematic review. Palliat Med. 2011;25(5):410–23.
Aitken M, et al. Medicines use and spending in the US: a review of 2015 and outlook to 2020. Parsippany: IMS Institute for Healthcare Informatics; 2016.
World Health Organization. WHO model list of essential medicines. Geneva: World Health Organization; 2017.
Gasse MC, et al. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy. 2000;20(6):629–34.
U.S. Food and Drug Administration. ULTRAM C IV (tramadol hydrochloride) Tablets. Silver Spring: U.S. Food and Drug Administration; 2017.
Cha HJ, et al. Dependence potential of tramadol: behavioral pharmacology in rodents. Biomol Ther. 2014;22(6):558.
Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol. Biol Psychol. 2006;73(1):90–9.
O’Connor EC, Mead AN. Tramadol acts as a weak reinforcer in the rat self-administration model, consistent with its low abuse liability in humans. Pharmacol Biochem Behav. 2010;96(3):279–86.
Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27(1):7–17.
Keup W. Missbrauchsmuster bei Abhängigkeit von Alkohol, Medikamenten und Drogen: Frühwarnsystem-Daten für die Bundesrepublik Deutschland 1976–1990. Freiburg: Lambertus-Verlag; 1993.
Cicero TJ, et al. A postmarketing surveillance program to monitor Ultram® (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend. 1999;57(1):7–22.
Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol in the management of pain. Drug Saf. 1996;15(1):8–29.
Fields H, Barbaro N, Heinricher M. Brain stem neuronal circuitry underlying the antinociceptive action of opiates, Progress in Brain Research. Amsterdam: Elsevier; 1988. p. 245–57.
Borazan NH, Furst DE. Nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. In: Katzung BG, Trevor AJ, editors. Basic and clinical pharmacology. San Francisco: McGraw-Hill Medical; 2014. p. 618–41.
Macintyre PE, Schug SA. Acute pain management: a practical guide. Boca Raton: CRC Press; 2015.
Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Investig. 2010;120(11):3779–87.
Haeseler G, et al. Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain. 2006;126(1–3):234–44.
Güven M, Mert T, Günay I. Effects of tramadol on nerve action potentials in rat: comparisons with benzocaine and lidocaine. Int J Neurosci. 2005;115(3):339–49.
Wang JT, et al. Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice. Can J Anesth. 2010;57(7):659–63.
Altunkaya H, et al. Comparison of local anaesthetic effects of tramadol with prilocaine for minor surgical procedures. Br J Anaesth. 2003;90(3):320–2.
Altunkaya H, et al. The postoperative analgesic effect of tramadol when used as subcutaneous local anesthetic. Anesth Analg. 2004;99(5):1461–4.
Pang W-W, et al. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med. 1998;23(6):580–3.
Pang W-W, et al. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med. 1999;24(3):246–9.
Jou I-M, et al. The effects of intrathecal tramadol on spinal somatosensory-evoked potentials and motor-evoked responses in rats. Anesth Analg. 2003;96(3):783–8.
Katsuki R, et al. Tramadol, but not its major metabolite (mono-O-demethyl tramadol) depresses compound action potentials in frog sciatic nerves. Br J Pharmacol. 2006;149(3):319–27.
de Jesús Pozos-Guillén A, et al. Analgesic efficacy of tramadol by route of administration in a clinical model of pain. In: Proceedings of Western Pharmacology Society. Western Pharmacology Society; 2005.
Marincsák R, et al. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg. 2008;106(6):1890–6.
Miyano K, et al. Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity. Anesth Analg. 2015;120(4):790–8.
Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, γ-aminobutyric acid A, and N-methyl-d-aspartate receptors expressed in Xenopus oocytes. Anesth Analg. 2005;100(5):1400–5.
Jesse CR, Nogueira CW. Evidence for the involvement of glutamatergic and neurokinin 1 receptors in the antinociception elicited by tramadol in mice. Pharmacology. 2010;85(1):36–40.
Ostadhadi S, et al. Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test. Brain Res Bull. 2017;134:136–41.
Okamoto T, et al. The inhibitory effects of ketamine and pentobarbital on substance P receptors expressed in Xenopus oocytes. Anesth Analg. 2003;97(1):104–10.
Minami K, et al. The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes. J Pharmacol Sci. 2011;115(3):421–4.
Sahbaie P, et al. Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision. Pain. 2009;145(3):341–9.
Cepeda MS, et al. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;3:005522.
Bianchi M, et al. Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol. Int Immunopharmacol. 2003;3(13–14):1901–8.
Schou WS, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.
Seybold V. The role of peptides in central sensitization. Sensory Nerves. Berlin: Springer; 2009. p. 451–91.
Greco MC, Navarra P, Tringali G. The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism. Life Sci. 2016;145:161–5.
Sawynok J, Reid AR, Liu J. Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice. Eur J Pharmacol. 2013;714(1–3):373–8.
Sawynok J. Adenosine receptor targets for pain. Neuroscience. 2016;338:1–18.
Khan Z, Ferguson C, Jones R. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia. 1999;54(2):146–65.
Smith H, Elliott J. Alpha2 receptors and agonists in pain management. Curr Opin Anesthesiol. 2001;14(5):513–8.
Faron-Górecka A, et al. Effects of tramadol on α2-adrenergic receptors in the rat brain. Brain Res. 2004;1016(2):263–7.
Berrocoso E, Micó JA, Ugedo L. In vivo effect of tramadol on locus coeruleus neurons is mediated by α2-adrenoceptors and modulated by serotonin. Neuropharmacology. 2006;51(1):146–53.
Sevcik J, et al. Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones. Br J Pharmacol. 1993;110(1):169–76.
Desmeules JA, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol. 1996;41(1):7–12.
Liu Y-M, et al. Effect of tramadol on immune responses and nociceptive thresholds in a rat model of incisional pain. J Zhejiang Univ Sci B. 2008;9(11):895–902.
Ceyhan D, et al. Comparison of the effects of curcumin, tramadol and surgical treatments on neuropathic pain induced by chronic constriction injury in rats. Turk Neurosurg. 2018;28:288–95.
Zhang J, et al. Tramadol and propentofylline coadministration exerted synergistic effects on rat spinal nerve ligation-induced neuropathic pain. PLoS One. 2013;8(8):e72943.
Mei X-P, et al. Depressing interleukin-1β contributed to the synergistic effects of tramadol and minocycline on spinal nerve ligation-induced neuropathic pain. Neurosignals. 2014;22(1):30–42.
Kraychete DC, et al. Proinflammatory cytokines in patients with neuropathic pain treated with Tramadol. Revista Brasileira de Anestesiologia. 2009;59(3):297–303.
St-Jacques B, Ma W. Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors. Exp Neurol. 2014;261:354–66.
Reinold H, et al. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Investig. 2005;115(3):673–9.
Telleria-Diaz A, et al. Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: involvement of prostaglandins and endocannabinoids. Pain. 2010;148(1):26–35.
Zhang Y, et al. Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. J Pharmacol Exp Ther. 1997;283(3):1069–75.
Bianchi M, et al. Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol. 1999;13(2):220–5.
Bianchi M, et al. Increased tumor necrosis factor-α and prostaglandin E2 concentrations in the cerebrospinal fluid of rats with inflammatory hyperalgesia: the effects of analgesic drugs. Anesth Analg. 2007;104(4):949–54.
Zhang L-Z, Guo Z. Tramadol reduces myocardial infarct size and expression and activation of nuclear factor kappa B in acute myocardial infarction in rats. Eur J Anaesthesiol (EJA). 2009;26(12):1048–55.
Sen S, et al. The efficacy of tramadol combined with a donor of NO, glyceryl trinitrate (GTN) mixture on cytokines, NF-κB expression and oxidative stress marker in the rat model of formalin-induced inflammation. Br J Med Med Res. 2013;3(4):1988–98.
Lee KM, et al. Spinal NF-κB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci. 2004;19(12):3375–81.
Lim H, et al. IKK/NF-κB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. Pain. 2017;158(9):1666–77.
Niederberger E, Geisslinger G. The IKK-NF-κB pathway: a source for novel molecular drug targets in pain therapy? FASEB J. 2008;22(10):3432–42.
Cury Y, et al. Pain and analgesia: the dual effect of nitric oxide in the nociceptive system. Nitric Oxide. 2011;25(3):243–54.
Miclescu A, Gordh T. Nitric oxide and pain: ‘something old, something new’. Acta Anaesthesiol Scand. 2009;53(9):1107–20.
Lamana SMS, et al. The anti-inflammatory effect of tramadol in the temporomandibular joint of rats. Eur J Pharmacol. 2017;807:82–90.
Yalcin I, Aksu F. Involvement of potassium channels and nitric oxide in tramadol antinociception. Pharmacol Biochem Behav. 2005;80(1):69–75.
Zhang J, et al. Tramadol differentially regulates M1 and M2 macrophages from human umbilical cord blood. Inflammopharmacology. 2017;25(5):533–41.
Kiguchi N, et al. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain. 2015;156(4):684–93.
Sakakiyama M, et al. Preventive and alleviative effect of tramadol on neuropathic pain in rats: roles of α2-adrenoceptors and spinal astrocytes. J Pharmacol Sci. 2014;124(2):244–57.
Mei X-P, et al. Combination of tramadol with minocycline exerted synergistic effects on a rat model of nerve injury-induced neuropathic pain. Neurosignals. 2013;21(3–4):184–96.
Macrae W. Chronic post-surgical pain: 10 years on. Br J Anaesth. 2008;101(1):77–86.
Koppert W. Opioid-induced hyperalgesia—pathophysiology and clinical relevance. Acute Pain. 2007;9(1):21–34.
Rivat C, Ballantyne J. The dark side of opioids in pain management: basic science explains clinical observation. Pain Rep. 2016;1(2):e570.
Grace PM, et al. Repeated morphine prolongs postoperative pain in male rats. Anesth Analg. 2019;128:161–7.
Grace PM, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci. 2016;113(24):E3441–50.
Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014;112(6):991–1004.
Romero-Alejo E, Puig MM, Romero A. Antihyperalgesic effects of dexketoprofen and tramadol in a model of postoperative pain in mice–effects on glial cell activation. J Pharm Pharmacol. 2016;68(8):1041–50.
Xu Y, et al. The spinal NR2BR/ERK2 pathway as a target for the central sensitization of collagen-induced arthritis pain. PLoS One. 2018;13(7):e0201021.
Bianchi M, Biella G, Panerai A. Hindpaw inflammation facilitates tail withdrawal reflexes induced by noxious thermal stimulation in the rat. Eur J Pain. 1994;15:77–81.
Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther. 1997;280(2):829–38.
Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther. 1992;263(1):136–46.
Kaneko M, et al. Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmacol Exp Ther. 2000;292(2):743–51.
Bianchi M, Panerai AE. Anti-hyperalgesic effects of tramadol in the rat. Brain Res. 1998;797(1):163–6.
Sousa AM, et al. Local effect of tramadol on formalin evoked flinching behavior in rats. Revista Brasileira de Anestesiologia. 2008;58(4):371–9.
Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52(1):77–92.
Barakat A, Hamdy MM, Elbadr MM. Uses of fluoxetine in nociceptive pain management: a literature overview. Eur J Pharmacol. 2018;829:12–25.
Hollingshead J, Dühmke R, Cornblath D. Tramadol for neuropathic pain. Cochrane Database Syst Rev. 2006;3:CD003726.
Mehta V, et al. Characterization of peripheral and central sensitization after dorsal root ganglion intervention in patients with unilateral lumbosacral radicular pain: a prospective pilot study. Br J Anaesth. 2017;118(6):924–31.
Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain. 2000;16(2 Suppl):S62–6.
Bailey M, et al. Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: a systematic review and meta-analysis of efficacy and safety. Pain. 2018;159(9):1696–704.
Inage K, et al. Low-dose tramadol and non-steroidal anti-inflammatory drug combination therapy prevents the transition to chronic low back pain. Asian Spine J. 2016;10(4):685–9.
Wilder-Smith CH, et al. Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination. Anesth Analg. 2003;97(2):526–33.
Lee SH, et al. Tramadol induced paradoxical hyperalgesia. Pain Physician. 2013;16(1):41–4.
Abreu M, et al. Tramadol-induced hyperalgesia and its prevention by ketamine in rats: a randomised experimental study. Eur J Anaesthesiol (EJA). 2015;32(10):735–41.
Roeckel L-A, et al. Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience. 2016;338:160–82.
Nijs J, et al. Treatment of central sensitization in patients with ‘unexplained’ chronic pain: what options do we have? Expert Opin Pharmacother. 2011;12(7):1087–98.
Moore R, McQuay H. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997;69(3):287–94.
Mattar OM, et al. Efficacy and safety of tramadol in pain relief during diagnostic outpatient hysteroscopy: systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2019;111:547–52.
Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications. Headache. 2012;52(3):467–82.
Sinert R, Blackstock U. Analgesia in patients with acute abdominal pain: to withhold or not to withhold? Ann Emerg Med. 2008;52(5):563–6.
Manterola C, et al. Analgesia in patients with acute abdominal pain. Cochrane Database Syst Rev. 2007;3:CD005660.
Golzari SE, et al. Therapeutic approaches for renal colic in the emergency department: a review article. Anesthesiol Pain Med. 2014;4(1):e16222.
Pathan SA, Mitra B, Cameron PA. A systematic review and meta-analysis comparing the efficacy of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the treatment of acute renal colic. Eur Urol. 2018;73(4):583–95.
Caraceni A, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13(2):e58–68.
Wiffen PJ, Derry S, Moore RA. Tramadol with or without paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017;5:CD012508.
Furlan AD, et al. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. Can Med Assoc J. 2006;174(11):1589–94.
Chou R, Huffman LH. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147(7):505–14.
Laxmaiah Manchikanti M, et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician. 2011;14(1):91–121.
Bravo L, Mico JA, Berrocoso E. Discovery and development of tramadol for the treatment of pain. Expert Opin Drug Discov. 2017;12(12):1281–91.
Close BR. Tramadol: does it have a role in emergency medicine? Emerg Med Australas. 2005;17(1):73–83.
Budd K. The role of tramadol in acute pain management. Acute Pain. 1999;2(4):189–96.
Davis JA, et al. Incidence and impact of pain conditions and comorbid illnesses. J Pain Res. 2011;4:331.
Scher AI, Stewart WF, Lipton RB. The comorbidity of headache with other pain syndromes. Headache. 2006;46(9):1416–23.
Gudala K, et al. High prevalence of neuropathic pain component in patients with low back pain: evidence from meta-analysis. Pain Physician. 2017;20:343–52.
Houmes R, et al. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg. 1992;74(4):510–4.
Kim H-J, et al. Comparative study of the efficacy of transdermal buprenorphine patches and prolonged-release tramadol tablets for postoperative pain control after spinal fusion surgery: a prospective, randomized controlled non-inferiority trial. Eur Spine J. 2017;26(11):2961–8.
Lanzetta A, et al. Intramuscular tramadol versus ketorolac in patients with orthopedic and traumatologic postoperative pain: a comparative multicenter trial. Curr Ther Res. 1998;59(1):39–47.
Hassan A, Wahba A, Haggag H. Tramadol versus celecoxib for reducing pain associated with outpatient hysteroscopy: a randomized double-blind placebo-controlled trial. Hum Reprod. 2015;31(1):60–6.
Grossi L, Cappello G, Marzio L. Premedication with tramadol in patients undergoing colonoscopy: a double-blind randomized placebo-controlled study. Dig Dis Sci. 2004;49(10):1641–5.
Vanhelleputte P, et al. Pain during bone marrow aspiration: prevalence and prevention. J Pain Symptom Manag. 2003;26(3):860–6.
Viegas O, Khaw B, Ratnam S. Tramadol in labour pain in primiparous patients. A prospective comparative clinical trial. Eur J Obstet Gynecol Reprod Biol. 1993;49(3):131–5.
Makkar JK, et al. Comparison of analgesic efficacy of paracetamol and tramadol for pain relief in active labor. J Clin Anesth. 2015;27(2):159–63.
Sunshine A, et al. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharmacol Ther. 1992;51(6):740–6.
Moore PA, et al. Tramadol hydrochloride: analgesic efficacy compared with codeine, aspirin with codeine, and placebo after dental extraction. J Clin Pharmacol. 1998;38(6):554–60.
Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets for dental pain. Anesth Prog. 2001;48(3):79.
Collins M, et al. The effect of tramadol on dento-alveolar surgical pain. Br J Oral Maxillofac Surg. 1997;35(1):54–8.
Robbins L. Tramadol for tension-type headache. Headache. 2004;44(2):192–3.
Engindeniz Z, et al. Intramuscular tramadol vs. diclofenac sodium for the treatment of acute migraine attacks in emergency department: a prospective, randomised, double–blind study. J Headache Pain. 2005;6(3):143–8.
Alemdar M, Pekdemir M, Selekler HM. Single-dose intravenous tramadol for acute migraine pain in adults: a single-blind, prospective, randomized, placebo-controlled clinical trial. Clin Ther. 2007;29(7):1441–7.
Johnston M, et al. Outpatient management of biliary colic: a prospective observational study of prescribing habits and analgesia effectiveness. Int J Surg. 2014;12(2):169–76.
Nicolás JT, et al. Intramuscular ketorolac compared to subcutaneous tramadol in the initial emergency treatment of renal colic. Archivos Espanoles de Urologia. 1999;52(5):435–7.
Gülen B, et al. Pain treatment in patients with acute pancreatitis: a randomized controlled trial. Turk J Gastroenterol. 2016;27(2):192–6.
Vergnion M, et al. Tramadol, an alternative to morphine for treating posttraumatic pain in the prehospital situation. Anesth Analg. 2001;92(6):1543–6.
Pagliara L, et al. Tramadol compared with diclofenac in traumatic musculoskeletal pain. Curr Ther Res. 1997;58(8):473–80.
Neri E, et al. Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial. Arch Dis Child. 2013;98(9):721–4.
Fowler M, et al. A rat model of full thickness thermal injury characterized by thermal hyperalgesia, mechanical allodynia, pronociceptive peptide release and tramadol analgesia. Burns. 2014;40(4):759–71.
Segu SS, et al. Analgesic efficacy and safety of lornoxicam injection versus tramadol injection in reducing pain during dressing of the burn wounds. Int J Med Pharm Sci. 2013;4(4):33–6.
Rodriguez RF, et al. Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: a double-blind comparative trial. Clin J Pain. 2008;24(1):1–4.
Bono A, Cuffari S. Effectiveness and tolerance of tramadol in cancer pain. A comparative study with respect to buprenorphine. Drugs. 1997;53:40–9.
Wilder-Smith C, et al. Oral tramadol, a μ-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol. 1994;5(2):141–6.
Göbel H, Stadler T. Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine. Drugs. 1997;53:34–9.
Wilder-Smith CH, Hill LT, Laurent S. Postamputation pain and sensory changes in treatment-naive patients characteristics and responses to treatment with tramadol, amitriptyline, and placebo. Anesthesiology. 2005;103(3):619–28.
Harati Y, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50(6):1842–6.
Kaneko K, et al. The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia. Neurosci Lett. 2014;562:28–33.
Russell IJ, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol. 2000;6(5):250–7.
Biasi G, et al. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res. 1998;18(1):13–9.
Schnitzer TJ, et al. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol. 2000;27(3):772–8.
Vorsanger G, et al. Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain. J Opioid Manag. 2008;4(2):87–97.
Überall MA, Mueller-Schwefe GH, Terhaag B. Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo-and active-controlled parallel-group phase IV study. Curr Med Res Opin. 2012;28(10):1617–34.
Fleischmann RM, et al. Tramadol for the treatment of joint pain associated with osteoarthritis: a randomized, double-blind, placebo-controlled trial. Curr Ther Res. 2001;62(2):113–28.
Beaulieu AD, et al. Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res Manag. 2008;13(2):103–10.
Kehlet H, Dahl JB. The value of” multimodal” or” balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77(5):1048–56.
Knotkova H, Pappagallo M. Adjuvant analgesics. Anesthesiol Clin. 2007;25(4):775–86.
Gilron I, Jensen TS, Dickenson AH. Combination pharmacotherapy for management of chronic pain: from bench to bedside. Lancet Neurol. 2013;12(11):1084–95.
Gong Y-H, et al. Antinociceptive effects of combination of tramadol and acetaminophen on painful diabetic neuropathy in streptozotocin-induced diabetic rats. Acta Anaesthesiol Taiwan. 2011;49(1):16–20.
López-Muñoz FJ, et al. Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat. Eur J Pharmacol. 2004;484(2–3):157–65.
Romero A, Miranda HF, Puig MM. Analysis of the opioid–opioid combinations according to the nociceptive stimulus in mice. Pharmacol Res. 2010;61(6):511–8.
Foroud M, Vesal N. Evaluation of the anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations using the tail-flick test in rats. in Veterinary Research Forum. Urmia: Faculty of Veterinary Medicine, Urmia University; 2015.
Wrzosek A, et al. Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain: an isobolographic analysis. J Physiol Pharmacol. 2009;60(4):71–8.
Miranda HF, et al. Antinociceptive interaction of tramadol with gabapentin in experimental mononeuropathic pain. Basic Clin Pharmacol Toxicol. 2016;119(2):210–4.
Hermeto LC, et al. Potentiation of epidural lidocaine by co-administering tramadol by either intramuscular or epidural route in cats. Can J Vet Res. 2015;79(3):214–20.
Chen Y, Chan SY, Ho PC. Isobolographic analysis of the analgesic interactions between ketamine and tramadol. J Pharm Pharmacol. 2002;54(5):623–31.
Farghaly H, et al. The effects of dexmedetomidine alone and in combination with tramadol or amitriptyline in a neuropathic pain model. Pain Physician. 2014;17(2):187–95.
Dürsteler C, et al. Synergistic interaction between dexamethasone and tramadol in a murine model of acute visceral pain. Fundam Clin Pharmacol. 2007;21(5):515–20.
McQuay H, Edwards J. Meta-analysis of single dose oral tramadol plus acetaminophen in acute postoperative pain. Eur J Anaesthesiol. 2003;20(S28):19–22.
Webb AR, et al. The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial. Anesth Analg. 2002;95(6):1713–8.
Dhillon S. Tramadol/paracetamol fixed-dose combination. Clin Drug Investig. 2010;30(10):711–38.
Varrassi G, et al. Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol. Curr Med Res Opin. 2017;33(6):1165–73.
López-Cedrún J, et al. Co-crystal of tramadol–celecoxib in patients with moderate to severe acute post-surgical oral pain: a dose-finding, randomised, double-blind, placebo-and active-controlled, multicentre, phase II trial. Drugs R&D. 2018;18(2):137–48.
Miranda H, et al. Interleukin-1beta in synergism gabapentin with tramadol in murine model of diabetic neuropathy. Inflammopharmacology. 2018. https://doi.org/10.1007/s10787-018-0532-7.
Acalovschi I, et al. Tramadol added to lidocaine for intravenous regional anesthesia. Anesth Analg. 2001;92(1):209–14.
Mao J, Gold MS. Combination drug therapy for chronic pain: a call for more clinical studies. J Pain. 2011;12(2):157–66.
Akbay BK, et al. Analgesic efficacy of topical tramadol in the control of postoperative pain in children after tonsillectomy. J Anesth. 2010;24(5):705–8.
Tekelioglu UY, et al. Comparison of topical tramadol and ketamine in pain treatment after tonsillectomy. Pediatr Anesth. 2013;23(6):496–501.
Gönül O, et al. Comparison of the effects of topical ketamine and tramadol on postoperative pain after mandibular molar extraction. J Oral Maxillofac Surg. 2015;73(11):2103–7.
Isiordia-Espinoza MA, et al. Preemptive analgesic effectiveness of oral ketorolac plus local tramadol after impacted mandibular third molar surgery. Medicina Oral Patologia Oral y Cirugia Bucal. 2011;16(6):e776–80.
Rashwan S, Abdelmawgoud A, Badawy AA. Effect of tramadol gargle on postoperative sore throat: a double blinded randomized placebo controlled study. Egypt J Anaesth. 2014;30(3):235–9.
Alagöl A, et al. The use of intraarticular tramadol for postoperative analgesia after arthroscopic knee surgery: a comparison of different intraarticular and intravenous doses. Knee Surg Sports Traumatol Arthrosc. 2004;12(3):184–8.
Akinci SB, et al. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005;21(9):1060–5.
Garlicki JA, et al. Effect of intraarticular tramadol administration in the rat model of knee joint inflammation. Pharmacol Rep. 2006;58(5):672.
Rayner L, et al. Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs. Pain. 2016;157(7):1472.
Castro M, et al. Comorbid depression and anxiety symptoms in chronic pain patients and their impact on health-related quality of life. Arch Clin Psychiatry (São Paulo). 2011;38(4):126–9.
Tsurko K, et al. The results of anxiolytic treatment in patients with chronic vertebrogenic low back pain syndrome. J Neurol Sci. 2013;333:e526–7.
Maruta T, Vatterott MK, McHardy MJ. Pain management as an antidepressant: long-term resolution of pain-associated depression. Pain. 1989;36(3):335–7.
Caspani O, et al. Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats. Pharmacol Biochem Behav. 2014;124:290–6.
Tetsunaga T, et al. Efficacy of tramadol–acetaminophen tablets in low back pain patients with depression. J Orthop Sci. 2015;20(2):281–6.
Yang C, et al. Tramadol pretreatment enhances ketamine-induced antidepressant effects and increases mammalian target of rapamycin in rat hippocampus and prefrontal cortex. BioMed Res Int. 2012;2012:175619.
Jayasree D, Rajeswaramma G. Effect of tramadol in elevated plus maze apparatus—a rodent model of anxiety. J Drug Discov Ther. 2015;3(27):3–7.
Shapira NA, Verduin ML, DeGraw JD. Treatment of refractory major depression with tramadol monotherapy. J Clin Psychiatry. 2001;62:205–6.
Rougemont-Bücking A, Gamma F, Panksepp J. Use of tramadol in psychiatric care: a comprehensive review and report of two cases. Swiss Med Wkly. 2017;147:w14428.
Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62(1):63–77.
Zanos P, et al. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227.
Bloms-Funke P, et al. Tramadol increases extracellular levels of serotonin and noradrenaline as measured by in vivo microdialysis in the ventral hippocampus of freely-moving rats. Neurosci Lett. 2011;490(3):191–5.
DeBattista C. Antidepressant agents. In: Katzung BG, Trevor AJ, editors. Basic and clinical pharmacology. San Francisco: McGraw-Hill Medical; 2014. p. 510–30.
Lopez MB. Postanaesthetic shivering–from pathophysiology to prevention. Roman J Anaesth Intensive Care. 2018;25(1):73.
Mohta M, et al. Tramadol for prevention of postanaesthetic shivering: a randomised double-blind comparison with pethidine. Anaesthesia. 2009;64(2):141–6.
Bhatnagar S, et al. Tramadol for postoperative shivering: a double-blind comparison with pethidine. Anaesth Intensive Care. 2001;29(2):149.
Nakagawa T, et al. The effects of tramadol on postoperative shivering after sevoflurane and remifentanil anesthesia. BMC Anesthesiol. 2017;17(1):1.
Witte JD, et al. Tramadol in the treatment of postanesthetic shivering. Acta Anaesthesiol Scand. 1997;41(4):506–10.
Yekkirala AS, et al. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017;16(8):545.
Yaksh TL, et al. The search for novel analgesics: targets and mechanisms. F1000prime Rep. 2015;7:56.
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Barakat, A. Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs 33, 481–501 (2019). https://doi.org/10.1007/s40263-019-00623-5
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DOI: https://doi.org/10.1007/s40263-019-00623-5