Paclitaxel-associated Acute Pain Syndrome Research Articles

Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice.

Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice. Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1-/- ) and B2 (B2-/- ), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4mg/kg, i.v.. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. Administration of PCX in B1-/- and B2-/- mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. Kinin-kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.

A pilot randomized, placebo-controlled, double-blind study of omega-3 fatty acids to prevent paclitaxel-associated acute pain syndrome.

e24115 Background: Paclitaxel, a widely used chemotherapeutic agent, is associated with an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is no standard of care for P-APS. Commonly used analgesics, including NSAIDs and narcotics, have considerable toxicity profiles. Omega-3 fatty acids, a common dietary supplement, have well established anti-inflammatory and neuroprotective properties. The primary aim of the study was to assess if omega 3 fatty acids could prevent P-APS. Methods: Patients scheduled to receive weekly paclitaxel (70-90mg/m2) were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior to starting paclitaxel and continued until paclitaxel was discontinued. Patients completed acute pain questionnaires at baseline, Days 2-7, prior to each subsequent treatment and one month after completion of therapy. The EORTC- QLQ CIPN 20 questionnaire was completed prior to each dose of paclitaxel and 1 month after completion. The primary objective was to compare the effect of omega 3 fatty acids, versus placebo, on the maximum pain score for the week following the 1st treatment and each subsequent paclitaxel treatment, and to compare pain medication use between the 2 arms. The secondary objective was to compare the effect of the intervention on the severity of CIPN. Results: 49 patients were randomized to treatment versus placebo. Linear mixed effects models were applied with the addition of a bootstrap approach to overcome limitations in the distributional assumptions to compare outcomes between treatment groups. Placebo results were similar to the reported natural history of P-APS. There was no significant difference in trends over time between the 2 groups in the maximum pain score at week 1 (p = .14) and over 12 weeks (p = .21). There was also no difference noted in the rates of use of over the counter analgesics (p = .39) and narcotics (p = .46). CIPN results did not differ between the 2 groups (p = .08). Conclusions: The results of this pilot study do not support the use of omega-3 fatty acids for the prevention of paclitaxel-associated pain syndrome. Clinical trial information: NCT01821833 .

Paclitaxel-activated astrocytes produce mechanical allodynia in mice by releasing tumor necrosis factor-\u03b1 and stromal-derived cell factor 1

BackgroundPaclitaxel is a widely used and potent chemotherapeutic agent for the treatment of cancer. However, patients receiving paclitaxel often develop an acute pain syndrome for which there are few treatment options. Astrocytes play an important role in the pathogenesis of pain in multiple preclinical models, as well as in paclitaxel-treated rodents. However, it is still unclear what the exact contribution of astrocytes may be in paclitaxel-associated acute pain syndrome (P-APS).MethodsP-APS was modeled by a single systemic or intrathecal injection of paclitaxel and astrocyte contribution tested by immunohistochemical, pharmacological, and behavioral approaches. Cell cultures were also prepared to assess whether paclitaxel treatment directly activates astrocytes and whether intrathecal injection of paclitaxel-treated astrocytes produces pain that is reminiscent of P-APS.ResultsSystemic injection of paclitaxel resulted in increased expression of glial fibrillary acidic protein (a common marker of astrocytic activation), as well as both systemic or intrathecal injection of paclitaxel induced pain hypersensitivity indicated by the development of mechanical allodynia, which was significantly reversed by the astrocytic inhibitor L-α-AA. Cultured astrocytes were activated by paclitaxel with significant increases in protein levels for tumor necrosis factor-α (TNF-α) and stromal-derived cell factor 1 (SDF-1). Importantly, intrathecal injection of paclitaxel-activated astrocytes produced mechanical allodynia that was reversed by TNF-α and SDF-1 neutralizing antibodies.ConclusionOur results suggest for the first time that paclitaxel can directly activate astrocytes, which are sufficient to produce acute pain by releasing TNF-α and SDF-1. Targeting astrocytes and these cytokines may offer new treatments for P-APS.

Efficacy of additional dexamethasone administration for the attenuation of paclitaxel-associated acute pain syndrome.

Paclitaxel-associated acute pain syndrome (P-APS) affects 80% of patients undergoing therapy. Although it has been shown that prednisone administration for 5days relieves P-APS, detailed results have not been reported thus far. Therefore, in this study, we evaluated the preventive effect of dexamethasone (DEX) administration against P-APS. A total of 60 patients who received carboplatin (area under the curve; AUC = 5-6) plus paclitaxel (200mg/m2) (plus bevacizumab 15mg/kg, if non-squamous carcinoma of lung) were enrolled. Eight milligrams of DEX was orally administered on days 2 and 3 to the DEX group patients, and the frequency, severity, duration of P-APS, and other adverse effects in the first cycle were retrospectively evaluated and compared to those observed in control group patients, who were not administered DEX on days 2 and 3. No difference in terms of patient characteristics, except for type of cancer, was observed between groups. The results showed that the frequency of all grade P-APS was approximately 70% and there was no difference between groups. Frequency of ≥ G2 P-APS was 40% in the control group and 14% in the DEX group, demonstrating a significant reduction. Duration of P-APS was 5.8days in the control group and 4.3days in the DEX group, which tended to become shorter following additional DEX administration, although this was not significant. Adverse effects other than P-APS induced by chemotherapy were similar between the two groups. Additional DEX administration is safe and useful for the attenuation of the severity of P-APS.

Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome.

Patients receiving paclitaxel for cancer treatment often develop an acute pain syndrome (paclitaxel-associated acute pain syndrome, P-APS), which occurs immediately after paclitaxel treatment. Mechanisms underlying P-APS remain largely unknown. We recently reported that rodents receiving paclitaxel develop acute pain and activation of spinal microglial toll like receptor 4 (TLR4) by paclitaxel penetrating into the spinal cord is a critical event in the genesis of P-APS. Our current study dissected cellular and molecular mechanisms underlying the P-APS. We demonstrated that bath-perfusion of paclitaxel, at a concentration similar to that found in the cerebral spinal fluid in animals receiving i.v. paclitaxel (2 mg/kg), resulted in increased calcium activity in microglia instantly, and in astrocytes with 6 min delay. TLR4 activation in microglia by paclitaxel caused microglia to rapidly release interleukin-1β (IL-1β) but not tumor necrosis factor α, IL-6, or interferon-γ. IL-1β release from microglia depended on capthepsin B. IL-1β acted on astrocytes, leading to elevated calcium activity and suppressed glutamate uptake. IL-1β also acted on neurons to increase presynaptic glutamate release and postsynaptic AMPA receptor activity in the spinal dorsal horn. Knockout of IL-1 receptors prevented the development of acute pain induced by paclitaxel in mice. Our study indicates that IL-1β is a crucial molecule used by microglia to alter functions in astrocytes and neurons upon activation of TLR4 in the genesis of P-APS, and targeting the signaling pathways regulating the production and function of IL-1β from microglia is a potential avenue for the development of analgesics for the treatment of P-APS.

Paclitaxel Induces Acute Pain via Directly Activating Toll like Receptor 4

Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients.

Paclitaxel-associated acute pain syndrome (P-APS) and its association on the development of peripheral neuropathy: NCCTG trial N08C1.

9047 Background: Paclitaxel is well known to cause an acute pain syndrome that has been referred to as arthralgias and myalgias. It has been hypothesized that this pain might actually be neurologic in origin (Loprinzi et al; Cancer J 2007; 13:399-403). A recent prospective cohort study evaluating the natural history of this paclitaxel-associated acute pain syndrome supported an association (p=0.0017) between the degree of paclitaxel-associated acute pain severity and the subsequent development of peripheral sensory neuropathy (Loprinzi et al; JCO, in press). Methods: Adult patients receiving at least 175 mg/m2 of paclitaxel every three weeks, with concomitant carboplatin, participated in this study. Patients completed questionnaires for 7 days following each dose of paclitaxel. They were asked to judge, on each day, pain that was new and that they thought was related to chemotherapy (graded on a scale of 0 to 10 with 10 being worst). They also completed questionnaires (EORTC CIPN-20 instrument) to collect neuropathy data at the beginning of each weekly cycle of therapy and monthly after chemotherapy completion. Descriptive statistics were utilized for study endpoints. Results: Eighty-five patients were accrued. Eighty-eight percent experienced pain, most prominent in the hips and lower extremities, which peaked at day 4 after the first paclitaxel cycle. Subjects who experienced less acute pain (scores of 0-4) with the first paclitaxel cycle had less neuropathy over 18 weeks of treatment than did patients with 5-10 pain score severities (Table). Conclusions: The paclitaxel-associated acute pain syndrome is common and does appear to be associated with the development of peripheral neuropathy. EORTC CIPN-20 endpoint Mean decrease in CIPN severity for P-APS score 0-4 (versus 5-10)* P value** Autonomic subscale 7.8 0.007 Motor subscale 7.9 0.004 Sensory subscale 11.3 0.001 Numbness—feet 17.0 0.001 Burning/shooting pain—feet 11.5 0.02 Tingling—feet 13.7 0.02 Numbness—hands 16.0 0.002 Burning/shooting pain—hands 8.7 0.02 Tingling—hands 11.0 0.04 * On a 0-100 point scale. ** Mixed modeling p values adjusted for age and race.

Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1.

The characteristics and natural history of the paclitaxel-acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. Patients receiving weekly paclitaxel (70 to 90 mg/m(2)) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) -20 instruments during the entire course of therapy. P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.

Natural history of paclitaxel-associated acute pain syndrome (P-APS): NCCTG trial N08C1.

9135 Background: Paclitaxel is well known to cause an acute pain syndrome that has, in the past, been referred to as arthralgias and myalgias. It has been hypothesized that this pain might actually...