Uses of fluoxetine in nociceptive pain management: a literature overview

Ahmed Barakat, Mostafa M. Hamdy, Mohamed M. Elbadr


PII: S0014-2999(18)30209-7
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.

[email protected] ahmedb[email protected] http://www.aun.edu.eg/membercv.php?M_ID=6116

*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.

1. Introduction

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.


Abdel-Salam, O.M., 2005. Anti-inflammatory, antinociceptive, and gastric effects of Hypericum perforatum in rats. The scientific world Journal 5, 586-595.
Abdel-Salam, O.M., Baiuomy, A.R., Arbid, M.S., 2004. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol. Res. 49, 119-131.

Abdel-Salam, O.M., Nofal, S.M., El-Shenawy, S.M., 2003. Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat. Pharmacol. Res. 48, 157-165. Abdel-Zaher, A.O., Mostafa, M.G., Farghaly, H.S., Hamdy, M.M., Abdel-Hady, R.H., 2013a.
Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav. Brain Res. 247, 17-26.
Abdel-Zaher, A.O., Mostafa, M.G., Farghly, H.M., Hamdy, M.M., Omran, G.A., Al-Shaibani, N.K., 2013b. Inhibition of brain oxidative stress and inducible nitric oxide synthase expression by thymoquinone attenuates the development of morphine tolerance and dependence in mice. Eur. J. Pharmacol. 702, 62-70.
Aghajanian, G.K., 1978. Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 276, 186-188.
Akaoka, H., Aston-Jones, G., 1993. Indirect serotonergic agonists attenuate neuronal opiate withdrawal. Neuroscience 54, 561-565.
Aksu, U., Guner, I., Yaman, O.M., Erman, H., Uzun, D., Sengezer-Inceli, M., Sahin, A., Yelmen, N., Gelisgen, R., Uzun, H., 2014. Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model. J. Physiol. Biochem. 70, 925- 934.
Akunne, H.C., Soliman, K.F., 1994. Serotonin modulation of pain responsiveness in the aged rat. Pharmacology Biochemistry and Behavior 48, 411-416.


Delivery and Therapeutics 6, 51-55.

Arends, R.H., Hayashi, T.G., Luger, T.J., Shen, D.D., 1998. Cotreatment with racemic fenfluramine inhibits the development of tolerance to morphine analgesia in rats. J. Pharmacol. Exp. Ther. 286, 585-592.
Arout, C.A., Edens, E., Petrakis, I.L., Sofuoglu, M., 2015. Targeting opioid-induced hyperalgesia in clinical treatment: neurobiological considerations. CNS drugs 29, 465-486. Begović, A., Zulić, I., Becić, F., 2004. Testing of analgesic effect of fluoxetine. Bosnian journal of basic medical sciences 4, 79-81.
Berry, P.H., Chapman, C., Covington, E., Dahl, J., Katz, J., Miaskowski, C., McLean, M., 2001. Pain: current understanding of assessment, management, and treatments. National Pharmaceutical Council and the Joint Commission for the Accreditation of Healthcare Organizations, VA, USA.
Bhargava, H.N., 1994. Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. Pharmacol. Rev. 46, 293-324.
BIANCHI, M., PANERAI, A.E., 1996. Antidepressant drugs and experimental inflammation. Pharmacol. Res. 33, 235-238.
Bianchi, M., Rossoni, G., Sacerdote, P., Panerai, A., Berti, F., 1995. Effects of chlomipramine and fluoxetine on subcutaneous carrageenin-induced inflammation in the rat. Inflamm. Res. 44, 466-469.
Bianchi, M., Sacerdote, P., Panerai, A.E., 1994. Fluoxetine reduces inflammatory edema in the rat: involvement of the pituitary-adrenal axis. Eur. J. Pharmacol. 263, 81-84.

Bickel, W.K., Stitzer, M.L., Liebson, I.A., Bigelow, G.E., 1988. Acute physical dependence in man: effects of naloxone after brief morphine exposure. J. Pharmacol. Exp. Ther. 244, 126-132. Biegon, A., Samuel, D., 1980. Interaction of tricyclic antidepressants with opiate receptors.
Biochem. Pharmacol. 29, 460-462.

Chazan, S., Ekstein, M., Marouani, N., Weinbroum, A., 2008. Ketamine for acute and subacute pain in opioid-tolerant patients. Journal of opioid management 4, 173-180.
Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The lancet 373, 746- 758.
Coda, B.A., Hill, H.F., Schaffer, R.L., Luger, T.J., Jacobson, R.C., Chapman, C.R., 1993. Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions. Pain 52, 85-91.
Conaghan, P.G., Peloso, P.M., Everett, S.V., Rajagopalan, S., Black, C.M., Mavros, P., Arden, N.K., Phillips, C.J., Rannou, F., van de Laar, M.A., 2014. 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 54, 270- 277.
Crespi, F., 2010. The selective serotonin reuptake inhibitor fluoxetine reduces striatal in vivo levels of voltammetric nitric oxide (NO): a feature of its antidepressant activity? Neurosci. Lett. 470, 95-99.

Cuéllar, B., Fernández, A.P., Lizasoain, I., Moro, M.A., Lorenzo, P., Bentura, M.L., Rodrigo, J., Leza, J.C., 2000. Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology (Berl.) 148, 66-73.
Deandrea, S., Montanari, M., Moja, L., Apolone, G., 2008. Prevalence of undertreatment in cancer pain. A review of published literature. Ann. Oncol. 19, 1985-1991.
Dhami, K., Churchward, M., Baker, G., Todd, K., 2013. Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult. Molecular and Cellular Neuroscience 56, 365-374.
Dirksen, R., Van Luijtelaar, E., Van Rijn, C., 1998. Selective serotonin reuptake inhibitors may enhance responses to noxious stimulation. Pharmacology Biochemistry and Behavior 60, 719- 725.
Dziedzicka-Wasylewska, M., Dlaboga, D., Pierzchala-Koziec, K., Rogoz, Z., 2002. Effect of tianeptine and fluoxetine on the levels of Met-enkephalin and mRNA encoding proenkephalin in the rat. J. Physiol. Pharmacol. 53, 117-126.
Erjavec, M.K., Coda, B.A., Nguyen, Q., Donaldson, G., Risler, L., Shen, D.D., 2000. Morphine‐ Fluoxetine Interactions in Healthy Volunteers: Analgesia and Side Effects. The Journal of Clinical Pharmacology 40, 1286-1295.
Gameiro, G.H., Gameiro, P.H., da Silva Andrade, A., Pereira, L.F., Arthuri, M.T., Marcondes, F.K., de Arruda Veiga, M.C.F., 2006. Nociception-and anxiety-like behavior in rats submitted to different periods of restraint stress. Physiol. Behav. 87, 643-649.

Gatch, M.B., Negus, S.S., Mello, N.K., 1998. Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys. Psychopharmacology (Berl.) 135, 99-106.
Gerra, G., Fertonani, G., Zaimovic, A., Rota-Graziosi, I., Avanzini, P., Caccavari, R., Delsignore, R., Lucchini, A., 1995. Hostility in heroin abusers subtypes: fluoxetine and naltrexone treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 19, 1225-1237.
Gharaei, B., Jafari, A., Aghamohammadi, H., Kamranmanesh, M., Poorzamani, M., Elyassi, H., Rostamian, B., Salimi, A., 2013. Opioid-sparing effect of preemptive bolus low-dose ketamine for moderate sedation in opioid abusers undergoing extracorporeal shock wave lithotripsy: a randomized clinical trial. Anesth. Analg. 116, 75-80.
Ghorbanzadeh, B., Mansouri, M.T., Naghizadeh, B., Alboghobeish, S., 2017. Local antinociceptive action of fluoxetine in the rat formalin assay: role of l-arginine/nitric oxide/cGMP/KATP channel pathway. Can. J. Physiol. Pharmacol., 1-8.
Gold, M., Redmond, D.E., Kleber, H., 1978. Clonidine blocks acute opiate-withdrawal symptoms. The lancet 312, 599-602.
Gordon, N.C., Heller, P.H., Gear, R.W., Levine, J.D., 1994. Interactions between fluoxetine and opiate analgesia for postoperative dental pain. Pain 58, 85-88.
Görlitz, B.-D., Frey, H.-H., 1972. Central monoamines and antinociceptive drug action. Eur. J. Pharmacol. 20, 171-180.
Gulur, P., Williams, L., Chaudhary, S., Koury, K., Jaff, M., 2014. Opioid tolerance–a predictor of increased length of stay and higher readmission rates. Pain physician 17, E503-E507.

Hache, G., Guiard, B.P., Le Dantec, Y., Orvoën, S., David, D.J., Gardier, A.M., Coudoré, F., 2012. Antinociceptive effects of fluoxetine in a mouse model of anxiety/depression.
Neuroreport 23, 525-529.

Harden, N., Cohen, M., 2003. Unmet needs in the management of neuropathic pain. J. Pain Symptom Manage. 25, S12-S17.
Harris, G.C., Aston-Jones, G., 2001. Augmented accumbal serotonin levels decrease the preference for a morphine associated environment during withdrawal.
Neuropsychopharmacology 24, 75-85.

Hutchinson, M.R., Lewis, S.S., Coats, B.D., Skyba, D.A., Crysdale, N.Y., Berkelhammer, D.L., Brzeski, A., Northcutt, A., Vietz, C.M., Judd, C.M., 2009. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain. Behav. Immun. 23, 240-250.
Huxtable, C., Roberts, L., Somogyi, A., MacIntyre, P., 2011. Acute pain management in opioid- tolerant patients: a growing challenge. Anaesth. Intensive Care 39, 804.
Hwang, A.S., Wilcox, G.L., 1987. Analgesic properties of intrathecally administered heterocyclic antidepressants. Pain 28, 343-355.
Hynes, M.D., Fuller, R.W., 1982. The effect of fluoxetine on morphine analgesia, respiratory depression, and lethality. Drug Development Research 2, 33-42.
Hynes, M.D., Lochner, M.A., Bemis, K.G., Hymson, D.L., 1985. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors. Life Sci. 36, 2317-2323.

Jain, A., Bhadauria, D., 2013. Evaluation of efficacy of fluoxetine in the management of major depression and arthritis in patients of Rheumatoid Arthritis. Indian Journal of Rheumatology 8, 165-169.
Jett, M.-F., McGuirk, J., Waligora, D., Hunter, J.C., 1997. The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization. Pain 69, 161-169. Jhamandas, K., Marsala, M., Ibuki, T., Yaksh, T., 1996. Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine. J. Neurosci. 16, 2758- 2766.
Johnston, I.N., Milligan, E.D., Wieseler-Frank, J., Frank, M.G., Zapata, V., Campisi, J., Langer, S., Martin, D., Green, P., Fleshner, M., 2004. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 24, 7353-7365.
Jones, C.K., Eastwood, B.J., Need, A.B., Shannon, H.E., 2006. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition. Neuropharmacology 51, 1172-1180.
Jovaiša, T., Laurinėnas, G., Vosylius, S., Šipylaitė, J., Badaras, R., Ivaškevičius, J., 2006. Effects of ketamine on precipitated opiate withdrawal. Medicina 42, 625-634.
Katzung, B.G.a.T., Anthony J., 2014 Basic and Clinical Pharmacology, 13th ed. McGraw-Hill Medical, San Francisco, USA.
Kehlet, H., Dahl, J.B., 1993. The value of” multimodal” or” balanced analgesia” in postoperative pain treatment. Anesth. Analg. 77, 1048-1056.

Kesim, M., Duman, E.N., Kadioglu, M., Ulku, C., Muci, E., Kalyoncu, N.I., Yaris, E., 2005. Antinociceptive effects of fluoxetine and paroxetine with their related actions on glycemia in mice. Neuro Endocrinol. Lett. 27, 281-287.
Kleber, H.D., 2007. Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues Clin. Neurosci. 9, 455.
Kolesnikov, Y.A., Pick, C.G., Ciszewska, G., Pasternak, G.W., 1993. Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor. Proceedings of the National Academy of Sciences 90, 5162-5166.
Kolesnikov, Y.A., Pick, C.G., Pasternak, G.W., 1992. NG-nitro-L-arginine prevents morphine tolerance. Eur. J. Pharmacol. 221, 399-400.
Koppert, W., Weigand, M., Neumann, F., Sittl, R., Schuettler, J., Schmelz, M., Hering, W., 2004. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth. Analg. 98, 1050-1055.
Kosiorek‐ Witek, A., Makulska‐ Nowak, H.E., 2016. Morphine analgesia modification in normotensive and hypertensive female rats after repeated fluoxetine administration. Basic Clin. Pharmacol. Toxicol. 118, 45-52.
Kostadinov, I., Delev, D., Petrova, M., Stanimirova, I., Draganova, M., Kruzliak, P., Kostadinova, I., Murdjeva, M., 2015. Study on anti-inflammatory and immunomodulatory effects of fluoxetine in rat models of inflammation. European Journal of Inflammation 13, 173- 182.

Küçükibrahimoğlu, E., Saygın, M.Z., Çalışkan, M., Kaplan, O.K., Ünsal, C., Gören, M.Z., 2009. The change in plasma GABA, glutamine and glutamate levels in fluoxetine-or S- citalopram-treated female patients with major depression. Eur. J. Clin. Pharmacol. 65, 571-577. Larcher, A., Laulin, J., Celerier, E., Le Moal, M., Simonnet, G., 1998. Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems. Neuroscience 84, 583-589.
Larson, A.A., Takemori, A., 1977. Effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake, on morphine analgesia and the development of tolerance. Life Sci. 21, 1807-1811.
Li, J.-X., Koek, W., Rice, K.C., France, C.P., 2011. Effects of direct-and indirect-acting serotonin receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in rhesus monkeys. Neuropsychopharmacology 36, 940.
Li, J.-Y., Wong, C.-H., Huang, E.Y.-K., Lin, Y.-C., Chen, Y.-L., Tan, P.P., Chen, J.-C., 2001.

Modulations of spinal serotonin activity affect the development of morphine tolerance. Anesth. Analg. 92, 1563-1568.
Liu, D., Wang, Z., Liu, S., Wang, F., Zhao, S., Hao, A., 2011a. Anti-inflammatory effects of fluoxetine in lipopolysaccharide (LPS)-stimulated microglial cells. Neuropharmacology 61, 592-599.
Liu, L., Coller, J.K., Watkins, L.R., Somogyi, A.A., Hutchinson, M.R., 2011b. Naloxone- precipitated morphine withdrawal behavior and brain IL-1β expression: comparison of different mouse strains. Brain. Behav. Immun. 25, 1223-1232.

Loeser, J.D., Treede, R.-D., 2008. The Kyoto protocol of IASP Basic Pain Terminology☆. Pain 137, 473-477.
Loyd, D.R., Henry, M.A., Hargreaves, K.M., 2013. Serotonergic neuromodulation of peripheral nociceptors, Semin. Cell Dev. Biol. Elsevier, pp. 51-57.
Loyd, D.R., Weiss, G., Henry, M.A., Hargreaves, K.M., 2011. Serotonin increases the functional activity of capsaicin-sensitive rat trigeminal nociceptors via peripheral serotonin receptors. PAIN® 152, 2267-2276.
Lu, Y., Ho, C.S., Liu, X., Chua, A.N., Wang, W., McIntyre, R.S., Ho, R.C., 2017. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS One 12, e0186700.
Lue, W.-M., Su, M.-T., Lin, W.-B., Tao, P.-L., 1999. The role of nitric oxide in the development of morphine tolerance in rat hippocampal slices. Eur. J. Pharmacol. 383, 129-135. Malec, D., Langwinski, R., 1980. Effect of quipazine and fluoxetine on analgesic‐ induced catalepsy and antinociception in the rat. J. Pharm. Pharmacol. 32, 71-73.
Manjunatha, C., 2010. A comparative study of antinociceptive activity of fluoxetine with diclofenac and pentazocine in rodent models.
Mansouri, M., Naghizadeh, B., Ghorbanzadeh, B., Alboghobeish, S., Houshmand, G., Amirgholami, N., 2017. Venlafaxine attenuates the development of morphine tolerance and dependence: role of L-arginine/nitric oxide/cGMP pathway. Endocr. Metab. Immune Disord. Drug Targets.
Marion Lee, M., Sanford Silverman, M., Hans Hansen, M., Vikram Patel, M., 2011. A comprehensive review of opioid-induced hyperalgesia. Pain physician 14, 145-161.

Martin, S.L., Power, A., Boyle, Y., Anderson, I.M., Silverdale, M.A., Jones, A.K., 2017. 5-HT modulation of pain perception in humans. Psychopharmacology (Berl.) 234, 2929-2939.
Maund, E., McDaid, C., Rice, S., Wright, K., Jenkins, B., Woolacott, N., 2011. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in
morphine-related side-effects after major surgery: a systematic review. Br. J. Anaesth. 106, 292- 297.
Maura, G., Raiteri, M., 1996. Serotonin 5‐ HT1D and 5‐ HT1A Receptors Respectively Mediate Inhibition of Glutamate Release and Inhibition of Cyclic GMP Production in Rat Cerebellum In Vitro. J. Neurochem. 66, 203-209.
Max, M.B., Lynch, S.A., Muir, J., Shoaf, S.E., Smoller, B., Dubner, R., 1992. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N. Engl. J. Med. 326, 1250-1256.
Mayer, D.J., Mao, J., Holt, J., Price, D.D., 1999. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proceedings of the National Academy of Sciences 96, 7731-7736.
Merskey, H.E., 1986. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Pain.
Messing, R., Phebus, L., Fisher, L., Lytle, L., 1975. Analgesic effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake. Psychopharmacol. Commun. 1, 511.

Messing, R.B., Fisher, L.A., Phebus, L., Lytle, L.D., 1976. Interaction of diet and drugs in the regulation of brain 5-hydroxyindoles and the response to painful electric shock. Life Sci. 18, 707-714.
Mitra, S., Sinatra, R.S., 2004. Perioperative management of acute pain in the opioid-dependent patient. The Journal of the American Society of Anesthesiologists 101, 212-227.
Mogil, J.S., 1999. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proceedings of the National Academy of Sciences 96, 7744-7751.
Mogil, J.S., Chesler, E., Wilson, S., Juraska, J., Sternberg, W., 2000. Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype. Neurosci. Biobehav. Rev. 24, 375-389.
Muscoli, C., Cuzzocrea, S., Ndengele, M.M., Mollace, V., Porreca, F., Fabrizi, F., Esposito, E., Masini, E., Matuschak, G.M., Salvemini, D., 2007. Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. The Journal of clinical investigation 117, 3530-3539.
Nayebi, A., Hassanpour, M., Rezazadeh, H., 2001. Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats. J. Pharm. Pharmacol. 53, 219-225.
Nayebi, A.M., Rezazadeh, H., Parsa, Y., 2009. Effect of fluoxetine on tolerance to the analgesic effect of morphine in mice with skin cancer. Pharmacol. Rep. 61, 453-458.
Ozdemir, E., Bagcivan, I., Gursoy, S., Altun, A., Durmus, N., 2011. Effects of fluoxetine and LY 365265 on tolerance to the analgesic effect of morphine in rats. Acta Physiol. Hung. 98, 205-213.

Patil, B.V., Binjawadgi, A., Kakkeri, R., Raikar, S., Anandi, B., 2013. A comparative study of analgesic activity of fluoxetine with ibuprofen and pentazocine in rodent models. Journal of Evolution of Medical and Dental Sciences 2, 6261-6270.
Pedersen, L.H., Nielsen, A.N., Blackburn-Munro, G., 2005. Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain. Psychopharmacology (Berl.) 182, 551-561.
Proudfit, H.K., Hammond, D.L., 1981. Alterations in nociceptirve threshold and morphine- induced analgesia produced by intrathecally administered amine antagonists. Brain Res. 218, 393-399.
Rafieian-Kopaei, M., 2000. Antinociceptive activity of antidepressants and correlation with neurotransmitter inhibitory potency. Medical Journal of The Islamic Republic of Iran (MJIRI) 13, 269-272.
Rani, P.U., Naidu, M., Prasad, V., Rao, T.R.K., Shobha, J., 1996. An evaluation of antidepressants in rheumatic pain conditions. Anesth. Analg. 83, 371-375.
Reinhold, K., Bläsig, J., Herz, A., 1973. Changes in brain concentration of biogenic amines and the antinociceptive effect of morphine in rats. Naunyn-Schmiedeberg’s archives of pharmacology 278, 69-80.
Rephaeli, A., Gil-Ad, I., Aharoni, A., Tarasenko, I., Tarasenko, N., Geffen, Y., Halbfinger, E., Nisemblat, Y., Weizman, A., Nudelman, A., 2009. γ-aminobutyric acid amides of nortriptyline and fluoxetine display improved pain suppressing activity. J. Med. Chem. 52, 3010-3017.

Rizzardo, A., Miceli, L., Bednarova, R., Guadagnin, G.M., Sbrojavacca, R., Della Rocca, G., 2016. Low-back pain at the emergency department: still not being managed? Ther. Clin. Risk Manag. 12, 183.
Rodrigues-Filho, R., Takahashi, R.N., 1999. Antinociceptive effects induced by desipramine and fluoxetine are dissociated from their antidepressant or anxiolytic action in mice. The The International Journal of Neuropsychopharmacology 2, 263-269.
Roumestan, C., Michel, A., Bichon, F., Portet, K., Detoc, M., Henriquet, C., Jaffuel, D., Mathieu, M., 2007. Anti-inflammatory properties of desipramine and fluoxetine. Respir. Res. 8, 35.
Sacre, S., Medghalchi, M., Gregory, B., Brennan, F., Williams, R., 2010. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll‐ like receptors. Arthritis & Rheumatology 62, 683-693.
Samanin, R., Gumulka, W., Valzelli, L., 1970. Reduced effect of morphine in midbrain raphe lesioned rats. Eur. J. Pharmacol. 10, 339-343.
Samanin, R., Valzelli, L., 1971. Increase of morphine-induced analgesia by stimulation of the nucleus raphe dorsalis. Eur. J. Pharmacol. 16, 298-302.
SAPUN, D.I., FARAH JR, J.M., MUELLER, G.P., 1981. Evidence that a serotonergic mechanism stimulates the secretion of pituitary β-endorphin-like immunoreactivity in the rat. Endocrinology 109, 421-426.
Savage, S.R., Joranson, D.E., Covington, E.C., Schnoll, S.H., Heit, H.A., Gilson, A.M., 2003. Definitions related to the medical use of opioids: evolution towards universal agreement. J. Pain Symptom Manage. 26, 655-667.

Sawynok, J., Esser, M., Reid, A., 1999. Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain 82, 149-158.
Schreiber, S., Pick, C.G., 2006. From selective to highly selective SSRIs: a comparison of the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram. Eur.
Neuropsychopharmacol. 16, 464-468.

Shen, F., Tsuruda, P.R., Smith, J.A., Obedencio, G.P., Martin, W.J., 2013. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model. PLoS One 8, e74891. Sikka, P., Kaushik, S., Kumar, G., Kapoor, S., Bindra, V., Saxena, K., 2011. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice.
Journal of Pharmacy and Bioallied Sciences 3, 412.

Sinatra, R., 2010. Causes and consequences of inadequate management of acute pain. Pain Med. 11, 1859-1871.
Singh, A.K., Zajdel, J., Mirrasekhian, E., Almoosawi, N., Frisch, I., Klawonn, A.M., Jaarola, M., Fritz, M., Engblom, D., 2017. Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain. The Journal of clinical investigation 127, 1370-1374.
Singh, V., Jain, N., Kulkarni, S., 2003a. Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/DA/serotoninergic pathways. Methods Find. Exp. Clin. Pharmacol. 25, 273-280.

Singh, V.P., Jain, N.K., Kulkarni, S., 2001. On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor. Brain Res. 915, 218-226.
Singh, V.P., Patil, C.S., Jain, N.K., Singh, A., Kulkarni, S.K., 2003b. Paradoxical effects of opioid antagonist naloxone on SSRI-induced analgesia and tolerance in mice. Pharmacology 69, 115-122.
Sivam, S., 1995. Serotonergic regulation of striatal dynorphin and substance P systems: a study with serotonin uptake inhibitor fluoxetine. Neurosci. Res. Commun. 17, 209-215.
Song, C., Halbreich, U., Han, C., Leonard, B., Luo, H., 2009. Imbalance between pro-and anti- inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 42, 182-188.
Sparkes, C., Spencer, P., 1971. Antinociceptive activity of morphine after injection of biogenic amines in the cerebral ventricles of the conscious rat. Br. J. Pharmacol. 42, 230-241.
Sugrue, M., McIndewar, I., 1976. Effect of blockade of 5‐ hydroxytryptamine re‐ uptake on drug‐ induced antinociception in the rat. J. Pharm. Pharmacol. 28, 447-448.
Suh, H., Tseng, L.-F., 1990. Intrathecal administration of thiorphan, bestatin, desipramine and fluoxetine differentially potentiate the antinociceptive effects induced by β-endorphin and morphine, administered intracerebroventricularly. Neuropharmacology 29, 207-214.
Tai, Y.-H., Wang, Y.-H., Wang, J.-J., Tao, P.-L., Tung, C.-S., Wong, C.-S., 2006. Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats. Pain 124, 77-86.
Tenen, S., 1968. Antagonism of the analgesic effect of morphine and other drugs by p- chlorophenylalanine, a serotonin depletor. Psychopharmacologia 12, 278-285.

Theesen, K.A., Marsh, W.R., 1989. Relief of diabetic neuropathy with fluoxetine. DICP 23, 572-574.
Tilson, H., Rech, R., 1974. The effects of p-chlorophenylalanine on morphine analgesia, tolerance and dependence development in two strains of rats. Psychopharmacology (Berl.) 35, 45-60.
Trujillo, K.A., Akil, H., 1991. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85-88.
Vogt, M., 1974. The effect of lowering the 5‐ hydroxytryptamine content of the rat spinal cord on analgesia produced by morphine. The Journal of physiology 236, 483-498.
Vos, T., Allen, C., Arora, M., Barber, R.M., Bhutta, Z.A., Brown, A., Carter, A., Casey, D.C., Charlson, F.J., Chen, A.Z., 2016. 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. The Lancet 388, 1545.
Voscopoulos, C., Lema, M., 2010. When does acute pain become chronic? Br. J. Anaesth. 105, i69-i85.
Wang, S.J., Su, C.F., Kuo, Y.H., 2003. Fluoxetine depresses glutamate exocytosis in the rat cerebrocortical nerve terminals (synaptosomes) via inhibition of P/Q‐ type Ca2+ channels. Synapse 48, 170-177.
Wang, Y.-X., Bowersox, S.S., Pettus, M., Gao, D., 1999. Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 291, 1008-1016.

WEIZMAN, R., PICK, C.G., 1996. The antinociceptive effects of fluoxetine. The Pain Clinic 9, 349-356.
Wen, Z.-H., Chang, Y.-C., Cherng, C.-H., Wang, J.-J., Tao, P.-L., Wong, C.-S., 2004.

Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats. Brain Res. 995, 253-259.
Wen, Z.-H., Wu, G.-J., Chang, Y.-C., Wang, J.-J., Wong, C.-S., 2005. Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats. Neuroscience 133, 807-817.
White, P.F., Kehlet, H., 2010. Improving Postoperative Pain ManagementWhat Are the Unresolved Issues? The Journal of the American Society of Anesthesiologists 112, 220-225. Wu, C.-C., Chen, J.Y.-R., Tao, P.-L., Chen, Y.-A., Yeh, G.-C., 2005. Serotonin reuptake inhibitors attenuate morphine withdrawal syndrome in neonatal rats passively exposed to morphine. Eur. J. Pharmacol. 512, 37-42.
Yaron, I., Shirazi, I., Judovich, R., Levartovsky, D., Caspi, D., Yaron, M., 1999. Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures. Arthritis Rheum. 42, 2561-2568.
Zalewska-Kaszubska, J., Górska, D., Dyr, W., Czarnecka, E., 2008. Lack of changes in beta- endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism–a pilot study. Die Pharmazie-An International Journal of Pharmaceutical Sciences 63, 308-311.
Zarrindast, M.-R., Sajedian, M., Rezayat, M., Ghazi-Khansari, M., 1995. Effects of 5-HT receptor antagonists on morphine-induced tolerance in mice. Eur. J. Pharmacol. 273, 203-207.

Zhao, Z.-Q., Chiechio, S., Sun, Y.-G., Zhang, K.-H., Zhao, C.-S., Scott, M., Johnson, R.L., Deneris, E.S., Renner, K.J., Gereau, R.W., 2007. Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. J. Neurosci. 27, 6045-6053.

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

-Hot plate

-Tail flick





-Serotonergic role

-Oipiodergic role

(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

-20 mg/kg



-Hargreaves test (+)

in wild type only

-Serotonergic role (Zhao et al., 2007)
-Mice -Cox -Swiss

-30 nmole

-Tail flick (0) -Serotonin exerts

(Hwang and

/♂/17-25 g



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

-Mice -ICR/♂/

-10-100 mg/kg-Hot plate (+)

-No opioidergic


25-35 g

I.P., S.C

-100-10000 ng I.T., I.C.V.

except for I.P.


PICK, 1996)

-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

-Albino/♀♂/-10 mg/kg



-10 mg/kg-Hot plate

-Hot plate(0)

(+)(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


120-130 g



-Oipiodergic role


- -Rhesus/♀♂/ -0.1-10 mg/kg -Tail flick (+) weak - Serotonergic role (Gatch et al.,

Monkey4.5-12 kg



Chemical pain model

-Mice-Laka /♀♂/ 20-


mg/kg-Writhing(+)-Serotonergic role

-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

-5-40 µg

- I.T.

- Repeated for 9 days
-Rats -Sprague- Dawley/-5, 10 mg/kg


(+) -Serotonergic role


120-130 g


-Capsaicin induced

-Oipiodergic role


-Single hind-paw licking

Electrical pain model

-Rats -Wistar/♂/

250–300 g

-0.5-4 mg/kg



-Noxious induced withdrawal reflexes

(-) (Dirksen et al.,

-Rats -Sprague-

Dawley/♂/ 120-130 g

-2.5, 5, 10




-Tail electric stimulation


at 5, 10 mg/kg

-Serotonergic role

-Opioidergic role

-Purinergic role

-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.,

CD /♂/




-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

-Hind paw



(Akunne andDawley/♂/ -I.P.pressureroleSoliman, 1994)3,25 month/ -Once daily200-500 g for 3 days

-Rats SHR/N/Ibm/Rw

and WKY/N

/♀♂ /

205 ± 35 and v285 ± 50 g

-5 mg/kg





(0) (Kosiorek‐

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

substance Plevel


Dawley/♂/-2.5, 5, 10


induced paw(+)

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

-20 mg/kg


-Once for 5

and 14 days

-120, 360 or

720 µg


Peripherally into the paw

-Mice DBA 1/♂/

8-12 week

-10, 25



-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

-60 mg



-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
-20 mg
-Rheumatic pain
-Unclear, dissociated
(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

Animal Strain/Gender/

species Age/WeightTreatment (dose, Test/

duration and route) OperationEffectProposed mechanismReferenceMorphine FluoxetineThermal pain model

-Mice -ICR/♂/

-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
-5 mg/kg
-0.32 mg/kg
-Serotonergic role
(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)

Morphine Fluoxetine

Electrical pain model

-21-40 years/ 10% of ideal body weight for height-Infusion pump deliver 15, 30,60
ng/ml-60 mg


-SingleStimuli were delivered to an upper central

weak-Serotonergic role(Erjavec et al., 2000)-I.V.-Single
Surgical pain model
-6 mg
-10 mg
-Dental extraction
-Altering morphine
(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



Age/WeightTreatment (dose,

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.,



pain model

-Cox Standard/-Once daily for 3 days

-1st day:32-Once daily for 3 days

-20 mg/kg




(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

and route)Test/




cespeciesMorphinNaloxoFluoxetinmeneneDevelopment of dependence

-Mice -Laka/♀♂/







(Singh20-30gmg/kgmg/kgmg/kg-Diarrhea(+)Interactionet al.,-S.C.-I.P.-I.P.between2003a)


daily for-Single

in 10th-Twice

daily fornitrergic,

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

daily for-Single

in 10th-Single

in 10thnitrergic,

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


in 5th-Single

in 5thstretching

-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.