Efficacy of Duloxetine in Conjunction With Tramadol for Chronic Cancer Pain

Cancer pain is one of the most common and problematic symptoms. Opioids are typically the most common drugs used in the treatment of cancer pain,they are limited due to their side effects. Tramadol is a centrally acting non-opiate analgesic with low affinity for μ-opioid receptors, and is effective in the treatment of moderate to severe pain. Neuropathic pain is typically not amenable to standard opiate therapy, and the addition of tricyclic antidepressants or/and antiepileptic drugs can offer a very effective treatment strategy in such patients. Duloxetine is a Serotonin Norepinephrine Reuptake Inhibitor (SNRI) that has been used traditionally for its antidepressant qualities and has also analgesic benefit in the treatment of neuropathic pain. Duloxetine exerts its analgesic action through central and peripheral pain modulation .

Cancer pain is one of the most common and problematic symptoms.uncontrolled pain affect quality of life and daily activities .Cancer pain has two main categories nociceptive and neuropathic pain,Cancer pain is often a combination of nociceptive and neuropathic pain. A framework for managing pain often starts with the World Health Organization (WHO) Analgesic Ladder, step 1 use non opioid analgesics, step 2 weak opioids, step 3 strong opioids, step 4 interventions non pharmacological, adjuvants can be added to any step . Opioids are typically the most common drugs used in the treatment of cancer pain. They work by binding to μ-opioid receptors within the central nervous system, which are responsible for opioid mediated analgesia, respiratory depression, sedation, physiological dependence, and tolerance, they are limited due to their side effects as nausea, constipation, sedation, and confusion, prolonged use of opioids may lead to development of tolerance, abnormal hypersensitivity to pain. Tramadol is a centrally acting non-opiate analgesic with low affinity for μ-opioid receptors, and is effective in the treatment of moderate to severe pain. It has been also shown to inhibit reuptake of serotonin and norepinephrine, which synergistically enhances its weak opioid mechanism of action. This may explain the reduced incidences of abuse, respiratory depression and other adverse effects of traditional opioids in patients on long-term tramadol therapy.it is a useful drug in patients with cancer pain both with nociceptive and neuropathic pain .Neuropathic pain is typically not amenable to standard opiate therapy, and the addition of tricyclic antidepressants or/and antiepileptic drugs can offer a very effective treatment strategy in such patients. Adjuvant analgesics are drugs primarily marketed for other indications, such as depression, but also have an important role in cancer pain management. Antidepressants, such as serotonin- norepinephrine reuptake inhibitors (duloxetine, venlafaxine) or tricyclics ( nortriptyline, amitriptyline) and anticonvulsants (pregabalin, gabapentin, carbamazepine) have efficacy in the treatment of pain, particularly neuropathic pain .Duloxetine is a Serotonin Norepinephrine Reuptake Inhibitor (SNRI) that has been used traditionally for its antidepressant qualities and has also analgesic benefit in the treatment of neuropathic pain . Duloxetine exerts its analgesic action through central and peripheral pain modulation , it enhances the effect of serotonin and norepinephrine on descending inhibitory pain pathways in the brain and spinal cord and activation of some cerebral prefrontal areas . Besides, it has been claimed that Duloxetine has an anti-nociceptive effect through Na + channel block , therefore it suppresses the neuronal cell firing resulting from peripheral injury . The most common adverse effects of duloxetine, which may lead to discontinuation of the drug, are nausea, dizziness, and somnolence .There is a possibility that duloxetine was effective in both activation of the descending pain modulatory system and the improvement of depressive mood, the effect may have partly taken place due to elevation of the pain threshold through the antidepressant effect of duloxetine . Recently, the efficacy of duloxetine has been reported in patients with chemotherapy-induced peripheral neuropathy (CIPN) and in non-cancer neuropathic pain. .

patients will receive tramadol 50 mg twice daily, titration will be done every 3days until 2 weeks, maximum dose will be 400mg daily and will receive duloxetine 30mg daily fixed dose in combination with tramadol. Investigators will follow up the patients for 3 months

patients will receive tramadol 50 mg twice daily, titration will be done every 3days until 2 weeks, maximum dose will be 400mg daily and will receive placebo drug once daily in combination with tramadol. Investigators will follow up the patients for 3 months

all participants(400 patients) will receive tramadol 50 mg twice daily, titration will be done every 3days until 2 weeks,according to changes in visual analogue scale for pain maximum dose will be 400mg daily, one group of participants(200 patients) will receive duloxetine 30mg daily fixed dose in combination with tramadol,decrease in concentration of tramadol consumption means better results,the other group(200 patients) will receive placebo drug once daily in combination with tramadol.

all participants(400 patients) will receive tramadol 50 mg twice daily, titration will be done according to changes in visual analogue scale for pain, maximum dose will be 400mg daily, one group of participants(200 patients) will receive duloxetine 30mg daily fixed dose in combination with tramadol,decrease in concentration of tramadol consumption means better results,the other group(200 patients) will receive placebo drug once daily in combination with tramadol.

subjective scale by the participants for pain intensity from 0 to 10, minimum value is zero that means no pain, maximum value is 10 that means unbearable pain, higher scores mean worse outcome

type of pain that responds better to duloxetine and tramadol (neuropathic or nociceptive), using visual analogue scale for pain intensity (subjective scale by the participants for pain intensity from 0 to 10, minimum value is zero that means no pain, maximum value is 10 that means unbearable pain, higher scores mean worse outcome)

used for neuropathic pain consists of seven questions minimum value 0 ,maximum value 24,scoring a score of 12 or more suggests pain of predominantly neuropathic origin

consisting of three questions for the participant,responses from 0 to 10 ,responses to three questions added then divided by three to get a mean score out of ten

consists of 9 questions for the participant ,This is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all," "several days," "more than half the days," and "nearly every day," respectively, total score for the nine items ranges from 0 to 27,higher scores means worse outcome

consists of 7 questions for the participant ,This is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all," "several days," "more than half the days," and "nearly every day," respectively, total score for the seven items ranges from 0 to 21,higher scores means worse outcome

consists of 16 items ,seven responses are delighted(7),pleased(6),mostly satisfied(5),mixed(4),mostly dissatisfied (3),unhappy(2),terrible(1),ranging from 16 to 112,average for healthy 90

participants will be asked about side effects from duloxetine as nausea,vomiting, constipation, sedation, (onset,duration,offset, bearable or not ,affecting quality of life), arrhythmia (type of arrhythmia from electrocardiogram ,onset,duration,offset),hypertension (by measuring blood pressure ,onset ,duration ,offset)

Inclusion Criteria: Patients with cancer pain age from 20-70 years old. not receiving any type of analgesia before (opioid naïve, no adjuvants). Exclusion Criteria: Difficult to be assessed for pain. Any contraindication for duloxetine or tramadol.

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