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Tapentadol in Chronic Pain Management
Recent research highlighting the role of descending noradrenergic pathways in the process of pain chronification suggests that drugs targeting norepinephrine reuptake could help restore balance within these pathways. Medications like tapentadol may work by enhancing spinal cord synaptic inhibition systems and preventing or reversing conditions that contribute to maladaptive synaptic plasticity. A Cochrane review on neuropathic pain has shown that combining two different mechanisms of action often results in superior effectiveness. The limited effectiveness of single-mechanism drugs, particularly for mixed pain types, stems from the fact that nociceptive and neuropathic pain have distinct pathogenic origins and require different treatment strategies.
Tapentadol, with its dual-action mechanism—μ-opioid receptor agonism and norepinephrine reuptake inhibition—offers an important therapeutic alternative to classical opioids like morphine and oxycodone. Its analgesic effectiveness is comparable to other strong opioids, but it has a significantly better side-effect profile, including a reduced potential for abuse. This favorable balance of efficacy and safety is likely due to the synergistic effect of its two mechanisms, allowing the use of an opioid with a lower affinity for μ-opioid receptors (about 50 times lower than morphine), which in turn reduces the risk of side effects, particularly gastrointestinal ones. Furthermore, tapentadol poses a low risk for drug interactions, making it especially suitable for patients on multiple medications.
Interestingly, tapentadol behaves differently from morphine in chronic treatment: it induces internalization of μ-opioid receptors, whereas morphine does not, suggesting distinct molecular mechanisms at the receptor level. Recent studies have also demonstrated tapentadol’s action at both central and spinal levels, making it an effective option for patients who have developed neuroplastic changes that alter pain pathways, rendering traditional analgesic treatments less effective. In a randomized trial, diabetic patients who stopped tapentadol after titration maintained a lower pain intensity compared to baseline, while those who continued treatment saw further reductions in pain intensity. Similar results were observed in another study. Niesters et al. conducted a trial with 24 patients suffering from diabetic polyneuropathy (DPN), who were randomized to receive either tapentadol sustained-release (SR) or placebo for four weeks. Pain modulation and analgesic responses were assessed before and after the treatment period.
Before treatment, none of the patients showed significant Conditional Pain Modulation (CPM). By week 4 of treatment, tapentadol SR significantly activated CPM, which coincided with notable pain relief. CPM increased from 9.1 ± 5.4% (baseline) to 14.3 ± 7.2% (placebo) and 24.2 ± 7.7% (tapentadol SR, p < 0.001 vs. placebo). Additionally, patients treated with tapentadol experienced greater relief from Diabetic Peripheral Neuropathy (DPN) pain compared to those on placebo (p = 0.028). The analgesic effect of tapentadol in chronic DPN pain was thus linked to the activation of descending inhibitory pain pathways, as indicated by the CPM responses. This dosage and treatment duration leverage the drug’s dual mechanisms: addressing pain symptoms and intervening in neuroplastic processes that contribute to pain chronification. Based on this, tapentadol at doses ranging from 50 mg to 250 mg twice daily (BID) may be effective for managing severe chronic pain, with the optimal median dosage being 150 mg BID for at least three months.
Conclusions: Ongoing research into the pathophysiological mechanisms of pain has highlighted the significance of central mechanisms, with a particular focus on the early stages of progression. This is important as early intervention with drugs like tapentadol, which offers two mechanisms of action and can be used at low doses, can help influence the neuroplastic changes that lead to pain chronification by blocking or slowing these processes. The availability of various dosages, including a recently introduced 25 mg formulation, allows clinicians to tailor treatment to individual patient needs and pain characteristics. This range of dosing options ensures optimal therapeutic management, particularly in the early stages of pain chronification and in the long-term management of chronic musculoskeletal pain (e.g., osteoarthritis and lumbago) and neuropathic pain.
Abstract:
Chronic pain is now understood as a neural disease, resulting from maladaptive functional and structural changes over time. In its chronic phase, pain becomes both a symptom and a disease in itself. Effective pain management is essential, as many patients continue to report inadequate pain relief despite ongoing treatments. Selecting the right therapy, considering the underlying pathophysiological mechanisms and the timing of intervention, is key to achieving successful pain control. This review will discuss the functional and structural changes leading to pain chronification, emphasizing the role of tapentadol in this process.
Materials and Methods:
Research studies included in this review were obtained through a keyword search of multiple databases (MEDLINE, Embase, Cochrane), with the last update conducted in November 2016. No restrictions were applied to the search criteria.
Functional and structural abnormalities in the nervous system, associated with pain chronification, have been observed in several conditions such as osteoarthritis, chronic back pain, chronic pelvic pain, and fibromyalgia. Proper identification and management of pain in its recurrent or progressive stages are crucial in preventing chronification and associated changes in neural structures. Among analgesic treatments, tapentadol, with its dual mechanism of action (opioid agonist and norepinephrine reuptake inhibitor), has shown effectiveness in controlling pain both centrally and spinally.
Conclusions:
Tapentadol is a promising option for patients in the early stages of progressive pain who have developed neuroplastic changes, altering pain pathways. The availability of various dosages of tapentadol allows clinicians to customize treatment according to the individual needs of each patient, enhancing the therapeutic effectiveness in managing musculoskeletal and neuropathic pain.
Pharmacokinetics in Hepatic Impairment:
The effects of mild and moderate hepatic impairment on the pharmacokinetics of tapentadol were explored in a single-dose study (HP5503/16). While dose proportionality in tapentadol pharmacokinetics has been established in healthy individuals, it had not been studied in those with hepatic impairment. To compare the results from the hepatic impairment study with other Phase I trials, pharmacokinetic parameters were normalized to the 80 mg dose used in the hepatic impairment study.
In a cross-study comparison, total systemic exposure (AUC∞ [mean ± SD]) to tapentadol was approximately 1.4 times higher in subjects with mild hepatic impairment (477 ± 266 ng•h/mL) and 3.5 times higher in those with moderate hepatic impairment (1171 ± 516 ng•h/mL), compared to subjects with normal hepatic function (334 ± 114 ng•h/mL).
The elimination half-life of tapentadol increased with worsening hepatic function. Subjects with moderate hepatic impairment had the longest half-life (6.2 ± 1.5 hours), compared to those with normal hepatic function (4.3 ± 0.76 hours) and mild hepatic impairment (5.1 ± 0.9 hours). The dose-normalized Cmax of tapentadol was almost the same in subjects with normal hepatic function (72.0 ± 29.0 ng/mL) and mild hepatic impairment (66.9 ± 22.4 ng/mL), but it was 1.8 times higher in subjects with moderate hepatic impairment (132 ± 58.6 ng/mL).