Uses of fluoxetine in nociceptive pain management: a literature overview
Ahmed Barakat, Mostafa M. Hamdy, Mohamed M. Elbadr
DOI: https://doi.org/10.1016/j.ejphar.2018.03.042 Reference: EJP71746
To appear in: European Journal of Pharmacology
Received date: 17 January 2018
Revised date: 28 March 2018
Accepted date: 29 March 2018
Cite this article as: Ahmed Barakat, Mostafa M. Hamdy and Mohamed M. Elbadr, Uses of fluoxetine in nociceptive pain management: a literature overview, European Journal of Pharmacology, https://doi.org/10.1016/j.ejphar.2018.03.042
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Uses of fluoxetine in nociceptive pain management: a literature overview
Ahmed Barakat*, Mostafa M. Hamdy, Mohamed M. Elbadr
Department of medical pharmacology, faculty of medicine, Assiut university, Assiut, 71526, Egypt.
*Corresponding author. Tel.: 002 01065125004; fax: 002 0882080278
Fluoxetine is one of the top ten prescribed antidepressants. Other therapeutic applications were approved for fluoxetine including, anxiety disorders, bulimia nervosa, and premature ejaculation. However, the role of fluoxetine in nociceptive pain management is still unclear. In this review, we discuss an overview of five possible roles of fluoxetine in pain management: intrinsic antinociceptive effect, enhancement of acute opioid analgesia, attenuation of tolerance
development to opioid analgesia, attenuation of dependence development and abstinence syndrome, and attenuation of opioid induced hyperalgesia.
Conflicting data were reported about fluoxetine intrinsic anti-nociceptive effect in preclinical and clinical studies except for inflammatory pain. Similar controversy was described in preclinical and clinical studies which explored the possible enhancement of opioid analgesia by fluoxetine co-administration. However, fluoxetine was found to have a promising effect on opioid tolerance and dependence in animal and human studies. Regarding opioid induced hyperalgesia, no studies examined fluoxetine effects in this regard.
Our literature review revealed that, the most likely beneficial use of fluoxetine in nociceptive pain management is for alleviation of inflammatory pain and attenuation of opioid tolerance and dependence. Non-steroidal anti-inflammatory and corticosteroids carry many adverse effects and toxicities. Effective alleviation of opioid tolerance and dependence represents a huge health burden and growing unmet medical need. Moreover, most agents used to attenuate these phenomena are either experimental or poorly tolerable drugs which limit their transitional value. Fluoxetine offers an effective, safe, and tolerable alternative for management of both inflammatory pain and opioid tolerance and dependence presently available to clinicians.
Keywords: Fluoxetine; Pain management; Opioid sparing effect; Opioid tolerance and dependence; Opioid induced hyperalgesia.
The international association for the study of pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Merskey, 1986). Pain exists in two forms: primary with no known precedent injury or pathology i.e., idiopathic e.g., some forms of chronic pain or secondary to tissue damage or other pathological factors. Secondary causes of pain encompass a wide variety of system-diseases from tension headache, migraine, otitis media, glaucoma, angina pectoris,
post-operative pain to gastritis, cystitis, and fibromyalgia. So, the scope of pain suffering is wide and implicated in several occasions of health care services. Despite the physiological functions of some pain aspects as an alarm signal and diagnostic indicator of health and integrity of human being, it represents a huge health burden.
One of the most reliable indicators of the overall pain burden is world health organization global burden of disease report, which measures diseases related disability. Disability is defined as any short or long-term health loss. This report measures disability-adjusted life years and years lived with disability for comparison between the burden of different diseases. An interesting finding in 2015 report is that, the leading cause of disability worldwide is pain (Table I) (Vos et al., 2016). Another finding is that pain has remained responsible for the highest disability years globally from 1990 through to 2015. Pain disorders as low back pain, neck pain, migraine, and musculoskeletal disorders were among the top 10 leading causes of disability (Table I) (Vos et al., 2016).
An added weight to the pain dilemma is that, despite increased attention paid to pain management, pain remains as an undertreated disorder. This suboptimal pain management was reported for different types of pain, from acute (Sinatra, 2010), cancer (Deandrea et al., 2008), low back pain (Rizzardo et al., 2016) to neuropathic (Harden and Cohen, 2003) and osteoarthritis pain (Conaghan et al., 2014). This rises the need for looking for other effective analgesics or strategies to control this dilemma.
Several systems are used for pain classification. The commonly used classifications are based on the underlying pathology (nociceptive and neuropathic), pain duration relative to tissue injury (acute and chronic), and intensity (mild, moderate, and severe). The focus of this review is on nociceptive pain.
The international association for the study of pain defines nociceptive pain as pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors (Merskey, 1986). Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system (Merskey, 1986).
Nociceptive pain is caused by stimulation of C and A nociceptors by noxious stimuli due to tissue damage or inflammation (Berry et al., 2001). In contrast to neuropathic pain, the somatosensory system does not have any lesion or pathology in nociceptive pain (Berry et al., 2001). Hence, good correlation exists between stimulus intensity and pain perception. Pain in this case is an expression of real tissue damage. Nociceptive pain is classified according to the site into superficial somatic (skin, mucous membranes, and subcutaneous tissue), deep somatic (muscles, joints, tendons, and bones), and visceral pain (visceral organs) (Berry et al., 2001).
Superficial pain is well localized pain with sharp or burning sensation as skin burns, cuts, and contusions (Berry et al., 2001). Localization of deep somatic pain is less than the superficial and may be diffuse as in arthritis and tendonitis pain (Berry et al., 2001). Visceral pain exists as well or poorly localized pain. Pain of visceral organs is dull aching or sharp stabbing pain and may be referred to other sites (Berry et al., 2001). Examples of visceral pain are abdominal colic, appendicitis, peptic ulcer, and cardiac ischemia. It should be noted that inflammatory pain also lies in the category of nociceptive pain (Loeser and Treede, 2008).
Inadequate nociceptive pain management has serious physiological, economic, and life quality consequences (Berry et al., 2001). Another important consequence is possible progression to chronic pain (Voscopoulos and Lema, 2010). Continuous unrelieved noxious stimuli lead to peripheral and central sensitization that initiate transformation to chronic pain. So, special attention has been paid off for rigorous treatment of nociceptive pain.
Major depressive disorder is the main indication of fluoxetine; however, there is a growing number of other applications for this agent (Cipriani et al., 2009). Fluoxetine was approved for treatment of some disorders like; posttraumatic stress disorder, generalized anxiety disorder, menopausal vasomotor symptoms, bulimia nervosa, and premature ejaculation (Katzung, 2014 ). Despite enormous researches, the role of fluoxetine in nociceptive pain management remains an ambiguous issue. In other words, could fluoxetine be used alone as an analgesic agent in nociceptive settings? Moreover, given the increased recognition of multimodal analgesia value, could fluoxetine combination with morphine adds to the overall pain management process? These questions are still not clearly answered.
Our literature review revealed five possible uses of fluoxetine in nociceptive pain management. These roles are: intrinsic antinociceptive effect when administered alone, enhancement of acute morphine analgesia, attenuation of tolerance development to morphine analgesia, attenuation of dependence development and associated abstinence syndrome, and amelioration of opioid induced hyperalgesia. The last four roles describe the value of combining fluoxetine with morphine. Morphine was selected since it is the prototype of opioid analgesics and primary analgesic in nociceptive pain management. The following discussion summarizes
the methodologies and main findings of the scientific literature; providing a conclusion and future directions for fluoxetine use in nociceptive pain management.
In the following discussion, both preclinical and clinical nociceptive pain studies were reviewed. Regarding preclinical nociceptive pain models, thermal, electrical, mechanical, chemical, and inflammatory pain models were reviewed.
2. Fluoxetine possible uses in nociceptive pain management
2.1. Intrinsic antinociceptive effect
The term “intrinsic antinociceptive effect” implies that, fluoxetine could exert an antinociceptive effect when administered alone either after a single or repeated administration. Approval of this use would provide an alternative to primary opioid and non-opioid analgesics with better tolerability and adverse effect profile e.g., fluoxetine does not carry the risk of
respiratory depression, tolerance, dependence, addiction, peptic ulceration, or drug induced pain
(Katzung, 2014 ). Table II and III reviews fluoxetine effects in different preclinical and clinical pain models.
Regarding preclinical findings (Table II), fluoxetine yielded contradictory and conflicting results. Hynes et al. (1985) reported that, fluoxetine analgesia depends on the employed test being effective in thermal and ineffective in electrical pain. Moreover, fluoxetine was found to be effective and ineffective in the same pain model employed. Thus, this discrepancy cannot be attributed simply to the specific sensory modality of the test employed. Hence, it is not clear what the contributing factors for this discrepancy may be; but, it might be attributed to the differences in species, strain, gender, weight, and age. These variables were reported to affect the antinociceptive activity (Mogil, 1999; Mogil et al., 2000). The employed dosage regimen (i.e., dose, route of administration, and duration) is another likely contributing factor which could affect analgesia results.
Another controversy exists in detecting the possible mechanism(s) of alleged fluoxetine analgesia. Two possible systems were suggested to mediate this effect, opioidergic and serotonergic systems. Regarding an opioidergic role, some investigators endorse this system as a possible mediator (Abdel-Salam et al., 2003; Ambirwar et al., 2016; Manjunatha, 2010; Singh et al., 2001). In support of this hypothesis, fluoxetine exerts naloxone-reversible antinociceptive effects. However, binding assay studies argued against this mechanism since the binding affinity of fluoxetine for opioid receptors was very low (Biegon and Samuel, 1980). Thus, fluoxetine might not exert direct opioidergic activity. On the other hand, indirect opioidergic activity through elevations in opioid peptides levels (enkephalin and endorphin) with fluoxetine single or repeated administration is a possible mediator (Dziedzicka-Wasylewska et al., 2002;
SAPUN et al., 1981). Given that, this fluoxetine induced changes in opioid peptides occurred at doses showed analgesic activity in different nociceptive tests. This indirect action was debated in another study (Zalewska-Kaszubska et al., 2008).
Additionally, serotonin is suggested to be another possible mediator (Hache et al., 2012; Manjunatha, 2010; Schreiber and Pick, 2006; Singh et al., 2001). This may be based on two possible mechanisms. First, serotonin is involved in nociceptive pain signaling via ascending and descending modulatory pathways (Martin et al., 2017). Serotonergic agents like fenfluramine were found to possess analgesic activity in different nociceptive models (Wang et al., 1999). Second, serotonin is also reported to affect relay of nociceptive signals to limbic structures, modulating the affective aspect of pain (Singh et al., 2017). This is in accordance with a hypothesis that fluoxetine-induced analgesia is due to alleviation of anxiety and depression (Hache et al., 2012), though other authors argued against this mechanism (Rodrigues-Filho and Takahashi, 1999). In short, fluoxetine’s serotonergic antinociceptive effect may be due to inhibition of both the sensory and affective (emotional) pain components. Further, morphine is well known to modulate both pain aspects; the emotional and sensory aspects. Previously, it was reported that morphine analgesia is mediated via serotonergic mechanisms (Coda et al., 1993; Li et al., 2011; Samanin and Valzelli, 1971; Sparkes and Spencer, 1971). This provides additional evidence that serotonin and in turn fluoxetine may have effects on the two pain aspects. Other investigators argued against fluoxetine serotonergic antinociceptive effect (Hwang and Wilcox, 1987; Rafieian-Kopaei, 2000). Their argument was based on a lack of correlation between serotonin transporter inhibitory activity and its analgesic activity.
One clinical trial reported that fluoxetine did not affect pain thresholds and decreased it in another study (Table III). These two trials did not explain their findings. A possible explanation of this discrepancy is that serotonin, the primary mediator of fluoxetine action, exerts both pro- and anti-nociceptive effects. The work of Hwang and Wilcox (1987) also came to the same conclusion. As discussed previously, serotonin anti-nociceptive effects are due to modulation of the two pain aspects, the affective (emotional) and sensory (perceptive) aspect. By contrast, serotonin pro-nociceptive effects were suggested to be mediated via its interaction and stimulation of peripheral nociceptors (Loyd et al., 2013; Loyd et al., 2011).
From table II, fluoxetine is found to be effective in the majority of inflammatory pain modes. This might be attributed to its intrinsic anti-inflammatory effect rather than direct action on nociceptors. The anti-inflammatory effect of fluoxetine was reported in other different settings as depression, lipopolysaccharide induced inflammation, and ischemia (Aksu et al., 2014; Liu et al., 2011a; Lu et al., 2017). Clinical trials employing inflammatory pain models as rheumatoid arthritis reported similar findings of animal studies, where fluoxetine was found have comparable efficacy to non-steroidal anti-inflammatory.
2.2. Multimodal analgesia value of fluoxetine – morphine combination
One of the widely employed strategies in pain management is the use of multi-modal analgesia (balanced analgesia) (Kehlet and Dahl, 1993). This term implies the use of more than one modality to control pain with the aim of enhancing the beneficial effects and reducing the adverse effects of overall pain management plan (Berry et al., 2001; Kehlet and Dahl, 1993; White and Kehlet, 2010). This could be achieved via administration of agents acting through different mechanisms. This section summarizes the potential merits of adding fluoxetine to
morphine, the primary analgesic for nociceptive pain, in common overall pain management strategies.
2.2.1. Enhancement of acute morphine analgesia
The use of morphine alone in treating nociceptive pain carries numerous adverse effects e.g., respiratory depression, nausea, vomiting, bradycardia, etc…, which greatly limits its clinical utility. Realization of this fact has led to using adjuvant analgesics in combination with morphine e.g., nonsteroidal anti-inflammatory drugs, local anesthetics, or ketamine with the aim of reducing the opioid dose and hence, its adverse effects i.e., opioid sparing effect (Gharaei et al., 2013; Koppert et al., 2004; Maund et al., 2011). Furthermore, this combinatorial approach is likely to increase the analgesic efficacy through addition of different antinociceptive mechanisms.
Hence, fluoxetine was combined with either effective or sub-effective morphine doses to study its effect on morphine analgesia in preclinical and clinical studies (Tables IV and V).
Most preclinical studies showed that fluoxetine exerts a potentiating effect on morphine analgesia as reported in different animal pain models (Table IV). A similar finding was reported in a clinical trial (Table V). This enhancement was attributed in the majority of studies to fluoxetine’s serotonergic effect. The relation between serotonin and morphine analgesia was described in several preclinical studies. Lowering serotonin activity through using neurotoxins, administration of serotonergic antagonists, or lesioning of serotonin containing nucleus was found to decrease morphine analgesia (Görlitz and Frey, 1972; Samanin et al., 1970; Tenen, 1968; Vogt, 1974). Similarly, facilitation of serotonergic activity via serotonin administration, serotonergic agonist, or stimulation of serotonin containing nucleus showed enhanced morphine
analgesia (Coda et al., 1993; Li et al., 2011; Samanin and Valzelli, 1971; Sparkes and Spencer, 1971). However, other investigators employing similar methodologies have obtained discrepant results concerning serotonin modulation of morphine analgesia (Proudfit and Hammond, 1981; Reinhold et al., 1973). Nonetheless, this finding was confirmed in a clinical trial (Table V).
2.2.2. Attenuation of tolerance development to morphine analgesia
Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time (Savage et al., 2003). Tolerance to opioids begins with the first dose and its pace increases with higher doses as well as shorter administration intervals which manifests clinically by higher opioid requirements to obtain the initial effect (Katzung, 2014 ). This hinders effective pain management with opioids. Previously, a study revealed that opioid-tolerant patients have longer hospital stays and greater remission rates compared to control patients i.e. did not receive opioid drugs (Gulur et al., 2014). Other studies raised concerns that persistent morphine administration results in a state called opioid-induced hyperalgesia (Marion Lee et al., 2011). Consequently, attenuation of tolerance development and controlling the increased opioid dose requirement is considered an integral part of an overall pain management plan (Huxtable et al., 2011).
Presently, no clinical trials were conducted to test fluoxetine’s possible effect in alleviating opioid tolerance. Most preclinical studies (Table VI) showed that fluoxetine combined with morphine attenuates tolerance development. This effect was attributed to fluoxetine’s serotonergic action. However, the role of serotonin in development of morphine tolerance is unclear. Enhancing serotonergic activity was found to exert either facilitatory or inhibitory effects on morphine tolerance. Intrathecal administration of serotonin facilitated
tolerance development (Li et al., 2001). On the other hand, serotonin releaser fenfluramine was found to attenuate morphine tolerance (Arends et al., 1998). Similarly, the serotonin depletor p- chlorophenylalanine, was found to inhibit morphine tolerance; nevertheless, it showed no effect in another study (Tilson and Rech, 1974; Zarrindast et al., 1995). Therefore, the serotoninergic system may not be fluoxetine’s primary target. Fluoxetine has effects on other systems including glutamate, infalmmatory status, oxidative stress, and nitric oxide which are well- known mediators of morphine tolerance (Abdel-Zaher et al., 2013a; Johnston et al., 2004; Larcher et al., 1998; Lue et al., 1999; Trujillo and Akil, 1991). These mechanisms might explain the efficacy of fluoxetine in attenuation of morphine tolerance. For example, fluoxetine was reported to decrease depolarization-evoked glutamate release (Wang et al., 2003). Another study reported that fluoxetine inhibited ischemia-induced glutamate release (Dhami et al., 2013). Among the attenuators of morphine tolerance are anti-inflammatory agents and nitric oxide synthase inhibitors (Kolesnikov et al., 1993; Wen et al., 2005). Hence, fluoxetine ability to diminish inflmmatory response and the elevation in nitric oxide could be a possible mechniam in attenauating morphine tolerance (Abdel-Salam et al., 2004; Crespi, 2010; Roumestan et al., 2007; Yaron et al., 1999). These proposed mechnisms were reported to mediate attenuation of tolerance by other antidepressants as amitriptyline and venlafaxine (Mansouri et al., 2017; Tai et al., 2006). However, preclinical and clinical studies are required to confirm this hypothesis.
2.2.3. Attenuation of dependence development and associated abstinence syndrome
Physical dependence is defined as a state of adaptation that often includes tolerance and is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt
cessation, rapid dose reduction, decreasing blood levels of the drug, and/or administration of an antagonist (Savage et al., 2003). Physical dependence is constant accompaniment of tolerance and the degree of dependence is related to the agonist intrinsic activity, dose, and administration frequency. Moreover, dependence was reported to develop after a single morphine dose in human subjects (Bickel et al., 1988).
Abstinence syndrome is an exaggerated rebound form of acute morphine effects. These withdrawal manifestations include autonomic and somatic symptoms such as rhinorrhea, lacrimation, hyperventilation, hypertension, tachycardia, hyperthermia, mydriasis, vomiting, diarrhea, muscle aches, hyperalgesia, etc… In addition to autonomic and somatic manifestations, affective symptoms ensue as dysphoria, anxiety, and depression (Katzung, 2014 ). The severity of abstinence syndrome depends largely on the degree of developed physical dependence.
Hence, abstinence syndrome could be viewed as an expression phase of physical dependence. Accordingly, administration of an opioid drug during the abstinence suppresses the withdrawal manifestations.
In addition to its distressful effects, abstinence syndrome results in hyperalgesia which compromise pain management, especially if expressed between administered doses. Hence, attenuation of development and expression of morphine dependence is a fundamental part of a common overall pain management plan (Huxtable et al., 2011).
All preclinical studies (Table VII) of fluoxetine showed a promising mitigating effect on the development and expression of morphine dependence. One clinical trial (Table VIII) tested fluoxetine’s effect on heroin (diamorphine) withdrawal-induced hostility and presented a similar favorable attenuating effect.
Most of these studies attributed fluoxetine’s effect to its serotonergic activity. Serotonin was reported to have an inhibitory effect on glutamate release (Maura and Raiteri, 1996).
Glutamate is a known mediator of opioid dependence (Abdel-Zaher et al., 2013b; Jhamandas et al., 1996; Wen et al., 2004). Further, it is widely known that norepinephrine-containing locus coeruleus neurons are responsible for somatic manifestations of morphine withdrawal and clonidine suppression of withdrawal symptoms (Aghajanian, 1978; Gold et al., 1978).
Serotonergic agents, like selective serotonin reuptake inhibitors and serotonin releaser fenfluramine, attenuated locus coeruleus hyperactivity directly and indirectly via diminishing glutamate input to locus coeruleus, both effects are mediated through increasing serotoninergic transmission (Akaoka and Aston-Jones, 1993).
Development and expression of morphine dependence was reported to occur concurrently with elevations in mediators such as nitric oxide and other inflammatory mediators’ levels (Cuéllar et al., 2000; Hutchinson et al., 2009; Liu et al., 2011b). So, fluoxetine-reported effects on these processes might contributes to its effect on morphine dependence. Preclinical and clinical studies are required to confirm this hypothesis.
2.2.4. Attenuation of opioid induced hyperalgesia
Opioid induced hyperalgesia is a paradoxical effect of opioid administration, where opioid drugs result in pro-nociceptive rather than anti-nociceptive response (Arout et al., 2015). Manifestations of this phenomenon are hyperalgesia, allodynia, diffusion of pain perception, and persistence of pain. Preclinical and clinical studies confirmed that opioid induced hyperalgesia develops after acute and chronic opioid administration. Naturally, this hyperalgesia would interfere with adequate pain management; hence, it is suggested that
attenuation of this phenomenon could be a target in overall pain management plan (Arout et al., 2015).
A critical issue in this regard, is the differentiation between development of opioid tolerance, opioid withdrawal-induced hyperalgesia, and opioid induced hyperalgesia. All three parameters share suboptimal pain relief outcome and are manifested with repeated opioid administration. However, preclinical and clinical studies indicated that their symptoms and management differ (Arout et al., 2015). In opioid tolerance, pain reappears with same intensity as pre-treatment level. Opioid dose escalation is the solution in this case. During repeated opioid administration, abstinence syndrome develops in the interval between doses resulting in withdrawal episodes of hyperalgesia. Treatment of this syndrome is via dose reduction (Arout et al., 2015). In opioid induced hyperalgesia, there is persistent hyperalgesia with chronic opioid administration. Increasing opioid dose in this case worsens the pain. So, the solution to this case is opioid cessation (Arout et al., 2015).
Unfortunately, we did not find in the literature any preclinical or clinical studies pertaining to fluoxetine effect in opioid induced hyperalgesia. However, studying the neurobiological mechanisms of this phenomenon reveals potential pathways that could be modulated by fluoxetine administration and hence speculating its potential effect.
Like opioid tolerance and dependence, opioid induced hyperalgesia is viewed as neuroadaptive response to opioid administration. These adaptive changes include central sensitization, increased spinal levels of dynorphin, microglial activation with pro-inflammatory response, and increased glutamatergic activity (Arout et al., 2015). Of these mechanisms, the
pro-inflammatory response and increased glutamatergic activity appear to be the most
promising targets for fluoxetine. Fluoxetine applied to microglial cell culture attenuated lipopolysaccharide induced glutamate, tumor necrosis factor alpha, and interleukin-1 release from microglial cells (Dhami et al., 2013; Liu et al., 2011a). In another clinical study fluoxetine was found to decrease glutamate and inflammatory cytokines release in depressed patients (Küçükibrahimoğlu et al., 2009; Song et al., 2009).
Fluoxetine effect on central sensitization is controversial, where conflicting data were reported (Jett et al., 1997; Zhao et al., 2007). On the other hand, fluoxetine was found to increase dynorphin level with repeated administration (Sivam, 1995). The impact of these data on development of opioid induced hyperalgesia is still unknown.
It was reported that opioid induced hyperalgesia and neuropathic pain share similar neurobiology (Arout et al., 2015; Mayer et al., 1999). Using this observation, fluoxetine studies in neuropathic pain could be a likely predictor of fluoxetine potential efficacy in opioid induced hyperalgesia. Fluoxetine efficacy in neuropathic pain was reported to be mild in some studies and absent in others (Max et al., 1992; Sawynok et al., 1999; Theesen and Marsh, 1989). Hence, fluoxetine might have little effect in alleviation of opioid induced hyperalgesia. It should be remembered that this only a speculation and animal and human studies are required to confirm this notion.
3. Value of using fluoxetine in nociceptive pain management
From our review of the literature, we conclude that the patient population most likely to benefit from fluoxetine are patients with inflammatory pain and opioid tolerant and dependent patients. Anti-inflammatory drugs typified be non-steroidal anti-inflammatory drugs and corticosteroids carry many adverse effects especially if intended for long term use as in rheumatic pain (Katzung, 2014 ). In contrast, fluoxetine long term safety and tolerability is well established, rendering it a practical alternative in this setting. Another likely benefit of fluoxetine in rheumatic pain is its ability to produce disease modifying effect in human and murine models of arthritis (Sacre et al., 2010). Clinical trials are required to compare the efficacy and tolerability of fluoxetine to standard anti-rheumatic drugs.
Attenuation of opioid tolerance and dependence has long remained an obstacle in the way of effective pain management. Several reports and guidelines have been published to control these phenomena and effectively achieve pain management in these patients (Huxtable et al., 2011; Mitra and Sinatra, 2004). Unfortunately, most agents that modify tolerance and dependence are experimental drugs used only in the laboratory animals which casts doubt on their translational value to clinical practice e.g., N-methyl-d-aspartate antagonist dizocilpine, nitric oxide synthase inhibitors, cytokines inhibitors, and antioxidants (Abdel-Zaher et al., 2013b; Bhargava, 1994; Hutchinson et al., 2009; Johnston et al., 2004; Kolesnikov et al., 1992; Muscoli et al., 2007; Trujillo and Akil, 1991). Other clinically used agents e.g., ketamine, clonidine, and opioid replacement carry many adverse effects and poor tolerability which challenge their utility (Chazan et al., 2008; Gold et al., 1978; Huxtable et al., 2011; Jovaiša et al., 2006; Katzung, 2014 ; Kleber, 2007). This highlights the need for seeking clinically useful alternatives with good safety and tolerability profile. Fluoxetine in this setting seems to be a better choice.
4. Future directions
Regarding fluoxetine, more clinical trials are required to further test the five possible roles of fluoxetine in pain management. To evaluate other antidepressants profile in pain management, we suggest this five-question system approach. Does this antidepressant exert analgesic activity either after single or repeated administration? Does this antidepressant enhance acute opioid analgesia? Does this antidepressant attenuate tolerance development to opioid analgesia? Does this antidepressant attenuate the development or expression of opioid dependence? Does this antidepressant attenuate opioid induced hyperalgesia? This approach will help to define the place of different antidepressants in nociceptive pain management process with its vast divisions.
The research was conducted through a special grant from grants office, faculty of medicine, Assiut university.
Conflicts of interest
The authors declare no conflicts of interest and no biomedical financial interest.
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Table I. Worldwide ten leading causes of disease related disability expressed as years lived with disability
No.Global leading causes (1990)Global leading causes (2005)Global leading causes (2015)
1 Lower back and neck painLower back and neck painLower back and neck pain2 Iron deficiency anemiaSense organs diseasesSense organs diseases3 Sense organs diseasesIron deficiency anemiaDepressive disorders4 Depressive disordersDepressive disordersIron deficiency anemia5 Skin diseasesSkin diseasesSkin diseases6 MigraineMigraineDiabetes7 Musculoskeletal disordersMusculoskeletal disordersMigraine8 Anxiety disordersDiabetesMusculoskeletal disorders9 DiabetesAnxiety disordersAnxiety disorders10 AsthmaAsthmaOral disorders
Table II. Preclinical studies on effect of fluoxetine on different models of nociceptive pain
Animal Strain /Gender
Test/ Operation Effect Proposed
(dose, duration and route)
Thermal Pain model
-Laka /♀♂/ 20- 30g
-Wistar/♀♂/ 180-200 g
-Single and once daily for 7 days
(Singh et al., 2001)
-Balb-c/♂/ 8-12 week
-Wistar/♂/ 8-10 week
-Single and once daily for 12 days
-Hot plate (+) Inverted U curve (> 10 mg/kg)
(Rephaeli et al., 2009)
-Mice -Wild-type and
Lmx1bf/f/p/♂/ 8-10 week
-Hargreaves test (+)
in wild type only
-Serotonergic role (Zhao et al., 2007)
-Mice -Cox -Swiss
-Tail flick (0) -Serotonin exerts
both pro- and anti- Wilcox, 1987) nociceptive effect
at spinal level
-Mice-ICR/♂/-1-100 mg/kg-Hot plate(+) weak-No opioidergic(Schreiber and25-35 g-I.P.Inverted UrolePick, 2006)-Singlecurve (> 75-Serotonergic rolemg/kg)-Adrenergic role-Mice-ICR/♂/-6 µg-Hot plate(0)(Suh and Tseng,23-25 g-I.T.-Tail flick(0)1990)-Single-Mice-Albino/-2,5,10 mg/kg-Tail flick(+)(Sikka et al.,♀♂/ 25-35 g-S.C.at 5 and 102011)-Singlemg/kg-MiceControl and-18 mg/kg-Hot plate(+)-Modulate pain(Hache et al.,CORT treated-Drinking-Cold plate(+)affective aspect2012)C57BL-6Jwater-Thermal(+)-Serotonergic role/♂/8–10 weeks-4 weekspreferenceonly inCORTtreated mice-Mice-Swiss/♂/-5,10,20-Hot plate(+)-Unclear but(Rodrigues-FilhoAdult/mg/kgat 10,20dissociated fromand Takahashi,30-40 g-I.P.-Tail flickmg/kgantidepressant1999)-Single(0)activity
-10-100 mg/kg-Hot plate (+)
-100-10000 ng I.T., I.C.V.
except for I.P.
-MiceAlbino/♀♂/-5 mg/kg-Hot plate(+)-Serotonergic role(Ambirwar et al.,25-30 g-S.C.-Opioidergic role2016)-Single-Mice-Balb-c/♀♂/-5,10, 20-Hot plate(+)-Unclear but(Kesim et al.,20-40 gmg/kgdissociated from2005)-I.P.glucose level-Single-Mice-Albino/♀♂/-5,10, 20-Hot plate(+)(Begović et al.,25-37 gmg/kg2004)-I.P.-Single-Rats-Sprague–10 mg/kg-Hot plate(+)-Serotonergic role(Akunne andDawley/♂/-I.P.Soliman, 1994)3,25 months/-Once daily200-500 gfor 3 days-Rats-Sprague-Dawley/-10 mg/kg-Tail flick(0)(Larson and200-300 g-I.P.Takemori, 1977)-Single-Rats-Sprague–3,10,30-Tail flick(+)(Pedersen et al.,Dawley/♂/mg/kgat 30 mg/kg2005)Adult-I.P.-Single-Rats-Cox-Sprague-10,20,40-Tail flick(0)-The analgesic(Hynes et al.,-Dawley/♀/mg/kgeffect is test1985)60-80 g-S.C.dependent-Single
-Rats-Wistar/♂/ 160-220 g
-10 mg/kg-Hot plate
(+)(Malec and Langwinski, 1980)
-Serotonergic role (Manjunatha,150 -200 g-I.P.-Opioidergic role 2010; Patil et al.,-Single-Inhibition of Nav, 2013)
Cav, Kv and Clv channel-Inhibition ofnicotinic receptor-Rats-CoxSprague–20 mg/kgTail flick(0)(Hynes andDawley/-S.C.Fuller, 1982)♀/60-80 g-Single-Rats-Wistar/♂/-0.5-4 mg/kg-Hot plate(0)(Dirksen et al.,250–300 g-I.V.-Tail flick(0)1998)-Single-Rats-Wistar/♂/-10 mg/kg-Hot plate(0)(Sugrue and50-60 g-I.P.McIndewar,-Single1976)
-Rats -Sprague- Dawley/-5, 10 mg/kg
-Hot plate (+) -Serotonergic role
- -Rhesus/♀♂/ -0.1-10 mg/kg -Tail flick (+) weak - Serotonergic role (Gatch et al.,
Chemical pain model
-Mice-Laka /♀♂/ 20-
-Oipiodergic role(Singh et al.,
2001)-Rats-Wistar/♀♂/-I.P.180-200 g-Single andonce daily for7 days-Mice-Cox Standard/-10, 20, 40-Writhing(0)(Hynes and20-22 gmg/kgFuller, 1982)-S.C.-Single-MiceICI-WSP/♂/-10-50 mg/kg-Writhing(+)-No correlation(Rafieian-Kopaei,22-25 g-S.C.between analgesia2000)-Singleandnorepinephrine,dopamine andserotonin activity-Mice-Swiss / ♀♂ / 30–5-40 mg/kg-Writhing(+)-Opioidergic role(Singh et al.,35 g-I.P.2003b)-Single
- Repeated for 9 days
-Rats -Sprague- Dawley/-5, 10 mg/kg
(+) -Serotonergic role
-Single hind-paw licking
Electrical pain model
-Noxious induced withdrawal reflexes
(-) (Dirksen et al.,
Dawley/♂/ 120-130 g
-2.5, 5, 10
-Tail electric stimulation
at 5, 10 mg/kg
-Blocking N- methyl-d-aspartate receptors
(Abdel-Salam et al., 2003)
-Rats -Electric shock (+) -Serotonergic role
-No opioidergic role
(Messing et al., 1975)
-Rats -Sprague- Dawley -10 mg/kg -Electric shock (+) -Serotonergic role (Messing et al.,
-Rats -Sprague- Dawley/-5, 10 mg/kg-Tail electric(+)-Serotonergic role(Abdel-Salam,120-130 g -S.C.stimulation-Oipiodergic role2005)-SingleMechanical pain model
-Rats -Sprague- -10 mg/kg
(Akunne andDawley/♂/ -I.P.pressureroleSoliman, 1994)3,25 month/ -Once daily200-500 g for 3 days
205 ± 35 and v285 ± 50 g
Witek and Makulska‐ Nowak, 2016)
Inflammatory pain model
-Mice-Wild-type and-20 mg/kg-Formalin test(0)-Serotonergic(Zhao et al.,Lmx1bf/f/p/♂/-I.P.early phaserole2007)8-10 week-Single-Formalin testlate phase(+)in wildtype only-Rats-Wistar/♂/-0.16, 0.32,-Formalin test(0)-Serotonergic(Nayebi et al.,275–300 g0.8 mg/kgearly phaserole2001)-Oral-Oipiodergic-Once daily-Formalin test(+)rolefor 7 dayslate phaseat-0.04, 0.08,repeated0.16 mg/kg0.8 mg/kg-I.P.orally,-Once dailyrepeatedfor 7 days0.16-0.32 mg/kgmg/kgand 10 µgI.P.,-Oral andsingleI.C.V.0.32
-Singlemg/kg orally and
single 10µg I.C.V.-Rats-Sprague–30–300-Formalin test(0)-Unclear(Sawynok et al.,Dawley/♂/nmolearly phase1999)100-200 g-Single-Formalin test(+)late phase-Rats-Wistar/♂/-10, 20, 100,-Formalin test(+)-Analgesic(Ghorbanzadeh130–160 g300 µg/pawearly phaseactivity in theet al., 2017)-Intraplantar-Formalin test(+)late phase is-Singlelate phasemediated via L-arginine/nitricoxide-cGMP-KATP pathway-Rats-Sprague–10 mg/kg-Formalin test(0)(Shen et al.,Dawley/♂/-I.P.late phase2013)Adult-Single-Rats-Control and-10 mg/kg-Formalin(+)-Serotonergic(Gameiro et al.,stressed-I.P.inducedrole2006)Wistar/♂/-Singleflinching and-Oipiodergic200–230 grubbingrole-Mice-Wild-type and-20 mg/kg-Carrageenan(+)-Serotonergic(Zhao et al.,Lmx1bf/f/p/♂/-I.P.inducedin wildrole2007)8-10 week-Singlemechanicaltype onlyhypersensitivity
-Rats-Sprague–0.3-10-Carrageenan(0)-Inhibition of(Jones et al.,Dawley/♂/mg/kginduced thermalboth2006)70-90 g-I.P.hyperalgesia andnorepinephrine-Singlemechanicaland serotonin isallodynianeeded to elicitanalgesicresponse-Rats-Sprague–3-30 mg/kg-Carrageenan(0)-Serotonin does(Jett et al.,Dawley/♂/-S.C.inducednot play a major1997)Adult-Singlehyperalgesiarole in centralpain-Rats-Sprague–2.5, 5, 10-Brewer’s yeast(+)-Anti-(BIANCHI andDawley CDmg/kginduced pawinflammatoryPANERAI,/♂/200-250 g-I.P.edemaaction due to1996; Bianchi-Singlestimulation ofet al., 1994)pituitaryadrenocorticalaxis-Rats-Sprague–5, 10, 20-Carrageenan(+)-Anti-(BIANCHI andDawley CDmg/kginduced pawinflammatoryPANERAI,/♂/200-250 g-I.P.edemaaction is1996; Bianchi-Singlemediated viaet al., 1995)reduction ofPGE2 and
Dawley/♂/-2.5, 5, 10
at 5, 10-Serotonin does
not play a major(Abdel-Salam
et al., 2003)120-130 g-I.P.edemamg/kgrole in-Singlemodulation ofinflammation-Anti-inflammatoryaction might bemediated viachanges in localmediatorsrelease-Rats-Wistar/♂/-5, 10, 20-Carrageenan(+)-Serotonergic(Kostadinov et220–250 gmg/kginduced pawat singleroleal., 2015)-I.P.edema20 mg/kg-Increase in-Single andand atinterlukin-10repeated forrepeatedand tumor14 daysdosesgrowth factor-βlevels-Decrease intumor necrosis-αlevel-Rats-Sprague–10, 20, 30,-Carrageenan(+)-Oipiodergic(Abdel-SalamDawley/60 mg/kginduced pawroleet al., 2004)120-130 g-I.P.edema-Single
-Once for 5
and 14 days
-120, 360 or
Peripherally into the paw
-Mice DBA 1/♂/
-Once daily for 7 days
Paw edema induced by collagen induced arthritis
(+) -Decrease in tumor necrosis factor, interleukin-6, and interferon- inducible protein 10
-Suppress signaling from toll-like receptor
(Sacre et al., 2010)
(+): increase pain threshold; (0): no effect on pain threshold; (-): decrease pain threshold
I.C.V.: intracerebroventricular; I.P.: intraperitoneal; I.T.: intrathecal; I.V.: intravenous; S.C.: subcutaneous.
Table III. Clinical studies on effect of fluoxetine on different models of nociceptive pain
Treatment (dose, duration and route)
Test/ Operation Effect Proposed mechanism Reference
Electrical pain model
-21-40 years/ 10% of ideal body weight for height
-Stimuli to an upper central incisor
(-) (Erjavec et al.,
Surgical pain model
-♀♂/-10 mg-Dental extraction(0)(Gordon et al.,21.4 ± 0.6 year/-Oralof mandibular third1994)139.8 ± 3.3 lb.-Once daily for 7molardays
Inflammatory pain model
(Rani et al.,40 ± 13 year-Oralfrom antidepressant1996)-Once daily for 1activitymonth-Direct analgesicactivity-♀/-20 mg-Rheumatic pain(+)-Antidepressant effect(Jain and33 ± 7 year-Oraldecreased painBhadauria,-Once daily forperception2013)24 weeks-Direct analgesicactivity
(+): increase pain threshold; (0): no effect on pain threshold; (-): decrease pain threshold
Table IV. Preclinical studies on the effect of fluoxetine on morphine induced analgesia
species Age/WeightTreatment (dose, Test/
duration and route) OperationEffectProposed mechanismReferenceMorphine FluoxetineThermal pain model
-0.96-2.19 -6 µg -Hot plate
-Morphine analgesia is
(Suh and23-25 gnmole -I.T. -Tail flick(+)mediated via spinalTseng, 1990)-I.C.V. -Singlenorepinephrine and-Singleserotonin and hot plateresponse issupraspinally mediated-Mice -Albino/-0.5 mg/kg -2 mg/kg -Tail flick(+)(Sikka et al.,♀♂/ 25-35g-S.C. -S.C.2011)-Single -Single-Mice -ICR/♂/Dose -0.5 mg/kg -Hot plate(+)(WEIZMAN25-35 gresponse -S.Cweakand PICK,curve -Single1996)-Mice -Albino/♀♂/-7 mg/kg -5 mg/kg -Hot plate(+)-Serotonergic role(Begović et al.,25-37 g-S.C. -I.P.2004)-Single -Single-Mice -Swiss/♀/-5 mg/kg -0.16, 0.32, -Hot plate(+)-Serotonergic role(Nayebi et al.,25±2 g-S.C. 0.64 mg/kg-Opioidergic role2009)-Single -I.P.-Single-Rats -Sprague–5 mg/kg -10 mg/kg -Hot plate(+)-Serotonergic role(Akunne andDawley/♂/-I.P. -I.P.Soliman, 1994)
3,25 month/-Single-Single200-500g-Rats-Sprague-Dose-10 mg/kg-Tail flick(+)-Serotonergic role(Larson and-Dawley/response-I.P.Takemori,200-300 gcurve-Single1977)-I.P.-Single-Rats-Cox-Sprague-0.5, 1, 2-10, 20, 40-Tail flick(+)-Serotonergic role(Hynes et al.,-Dawley/♀/mg/kgmg/kg1985)60-80g-S.C.-S.C.-Single-Single-Rats-Wistar/♂/-8 mg/kg-10 mg/kg-Hot plate(+)-Serotonergic role(Malec and160-220g-I.P.-I.P.Langwinski,-Single-Single1980)-Rats-Cox-Sprague-0.25, 0.5, 1,-10, 20, 40-Tail flick(+)-Serotonergic role(Hynes and-Dawley/♀/2 mg/kgmg/kgFuller, 1982)60-80g-S.C.-S.C.-Single-Single-Rats-Wistar/♂/-3 mg/kg-10 mg/kg-Hot plate(+)-Serotonergic role(Sugrue and50-60 g-S.C.-I.P.McIndewar,-Single-Single1976)–Rhesus/-0.1–10-3.2 mg/kg-Tail flick(+)-Serotonergic role(Gatch et al.,Monkey♀♂/mg/kg-Singleweak1998)4.5-12 kgCumulative
Chemical pain model
-Mice-Cox Standard/-Dose-10, 20, 40-Writhing(+)-Serotonergic role(Hynes and20-22 gresponsemg/kgFuller, 1982)curve-S.C.-S.C.-Single
Electrical pain model-Rats-Electric(+)-Serotonergic role(Messing et al.,shock1975)Mechanical pain model-Rats -Sprague–5 mg/kg-10 mg/kg-Hind paw(+)-Serotonergic role(Akunne andDawley/♂/-I.P.-I.P.pressureSoliman, 1994)3,25 months/-Single-Single200-500g-Rats SHR/N/Ibm/Rw-5 mg/kg-5 mg/kg-Randall–(-)(Kosiorek‐and WKY/N-Oral- S.C.Selitto testWitek and/♀♂/-Once daily-SingleMakulska‐205 ± 35 andfor 4 and 8Nowak, 2016)v285 ± 50 gdays
Inflammatory pain model
(Nayebi et al.,275–300 g-I.P.-I.P.test early2001)-Single-Singlephase(+)-Formalintest latephase-Rats-Dose-10 mg/kg-Formalin(0)-Balance between(Shen et al.,response-I.P.test lateserotonergic and2013)
-Single phase noradrenergic activity is
required to enhance morphine antinociception
(+): increase morphine analgesia; (0): no effect on morphine analgesia; (-): decrease morphine analgesia I.C.V.: intracerebroventricular; I.P.: intraperitoneal; I.T.: intrathecal; I.V.: intravenous; S.C.: subcutaneous.
Table V. Clinical studies on the effect of fluoxetine on morphine induced analgesia
Treatment (dose, duration Test/ Operation Effect Proposed mechanismReference and route)
Electrical pain model
-21-40 years/ 10% of ideal body weight for height-Infusion pump deliver 15, 30,60
-SingleStimuli were delivered to an upper central
weak-Serotonergic role(Erjavec et al., 2000)-I.V.-Single
Surgical pain model
(Gordon et21.4 ± 0.6 year/-I.V.-Oralof mandibular thirdmetabolism andal., 1994)139.8±3.3 lb.-Single-Once dailymolardistributionfor 7 days
(0): no effect on morphine analgesia; (-): decrease morphine analgesia I.V.: intravenous
Table VI. Preclinical studies on the effect of fluoxetine on tolerance development to morphine analgesia
duration and route)Test/
mechanismReferenceMorphine FluoxetineThermalPain model-Mice-Swiss/♀-5 mg/kg -0.16, 0.32,-Hot plate(+)-Fluoxetine(Nayebi et25 ± 2 g-I.P. 0.64 mg/kgprevental., 2009)-Once daily -I.P.tolerancefor 30 days -Once dailyinducedfor 30 daysdecrease inserotonin level-Mice-Laka/♀♂/-10 mg/kg -10 mg/kg-Tail flick(+)-Interaction(Singh et20-30g-S.C. -I.P.betweenal., 2003a)-Twice -Twice dailynitrergic anddaily for 9 for 9 daysserotonergicdays and single in
10th daysystems-Rats-Sprague-75 mg -10 mg/kg-Tail flick(-)-No(LarsonDawley/pellet -I.P.serotonergicand200-300 g-S.C. -Once dailyrole inTakemori,-Two pellets for 3 daysdevelopment of1977)in 3 daystolerance-Rats-Wistar/♂/-50 mg/kg -10 mg/kg-Hot plate(+)(Ozdemir170-190g-S.C. -I.P.-Tail flick(+)et al.,
-Cox Standard/-Once daily for 3 days
-1st day:32-Once daily for 3 days
(Hynes and20-22 gmg/kg four-S.C.roleFuller,times1982)-2nd day:64mg/kg threetimes + 96mg/kg-S.C.
(+): attenuate morphine tolerance development; (-): facilitate morphine tolerance development.
I.P.: intraperitoneal; S.C.: subcutaneous.
Table VII. Preclinical studies on the effect of fluoxetine on development and expression of morphine dependence
eightTreatment (dose, duration
cespeciesMorphinNaloxoFluoxetinmeneneDevelopment of dependence
serotonergi9 daysday9 daysc anddopaminergicsystemsExpression of dependence-Mice -Laka/♀♂/-10-2-10-Jumping(+)-(Singh20-30gmg/kgmg/kgmg/kg-Diarrhea(+)Interactionet al.,-S.C.-I.P.-I.P.between2003a)-Twice
serotonergi9 daysdaydayc anddopaminergicsystems-Rats Born to(Passive-1-20, 40-(+)-(Wu etNeonat -Sprague-Dawley/♀/exposure)mg/kgmg/kgAbdominaSerotonergal.,es 200-250 g-2 mg/kg-S.C.-S.C.l(+)ic role2005)(before
-Yawning-3 mg/kgdayday(afterconception)-4 mg/kg
delivery)-S.C.-Twicedaily for7,conception periodand 5daysrespectively-Rats-Sprague-Dawley/♂/-75 mg-Not-3.5, 10-(+)-(Harris200-250 gpelletusedmg/kgconditioneSerotonergand-S.C.–I.P.d placeic roleAston–TwoRemov-Singlepreference(+)Jones,pelletsal ofin testfor2001)for 14pelletsdaywithdrawadayslenvironment-Buryingresponse-Rats-6 days-0.1-4 mg/kg-(+)-Enhanced(Akaokamg/kg-I.V.Withdrawserotonergiand-I.V.al inducedc activityAston-
in 5th day
ity of locus coeruleus
glutamate influence on locus coeruleus
(+): attenuate morphine dependence; (0): no effect on morphine dependence. I.P.: intraperitoneal; I.V.: intravenous; S.C.: subcutaneous.
Table VIII. Clinical studies on the effect of fluoxetine on development and expression of morphine dependence
Gender/Treatment (dose, duration and route)Test/EffectProposedReferenceAge/Wt.Heroin Naloxone/Naltrexone FluoxetineOperationmechanism♂/19-28-1-2 g Naloxone -40 mg-Hostility(0)-(Gerra etyears(18% -0.04+0.2 mg -OrallytowardsSerotonergical., 1995)purity) -I.V. -Once daily
-Daily -In 3th day for 3others
(+)rolefor 4-6 + monthstowardsyears Naltrexoneself-10-50 mg-Orally
-In 4th and 5th day then50 mg daily for 6months
(+): attenuate morphine dependence; (0): no effect on morphine dependence.