Clearly identify and accurately describe in detail at least two strategies that you would use that you found to be effective in finding peer-reviewed research.

European Review for Medical and Pharmacological Sciences

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Abstract. – OBJECTIVE: Chronic pain is one of the most common complaints for people seek- ing medical care, with a series of potential detri- mental effects on the individual and his social texture. Despite the heavy impact of chronic pain on patients’ quality of life, epidemiological data suggest that chronic pain is often untreated or undertreated. An accurate diagnostic flow and appropriate treatment should be considered as key factors for optimal management of patients with chronic pain. Opioids are recommended for treatment of chronic cancer pain (CCP) and chronic non-cancer pain (CNCP) in guidelines and can safely and effectively relieve pain in a number of patients with chronic pain. Converse- ly, fears of addiction and adverse events could result in ineffective pain management. Recent epidemiological and clinical data demonstrate that only low percentages of patients treated with opioids for chronic pain have a risk to de- velop addiction, with a prevalence rate similar to that observed in the general population.

METHODS: Despite the iatrogenic risk can be considered as low, validated tools for the early identification of patients at higher risk of addic- tion can help health professionals in the overall management of chronic pain.

CONCLUSIONS: Due to the increasing rele- vance of primary care physicians in chronic pain management, we propose a 28-item question- naire to validate specifically conceived for GPs’ and aimed at the preliminary evaluation of the risk of addiction in patients with chronic pain.

Key Words: Pain management, Opioid, Quality of life.

Introduction

Chronic pain (CP) is a widespread pathologi- cal condition and a public health issue, with

Opioid risk addiction in the management of chronic pain in primary care: the addition risk questionnaire

C. LEONARDI1, R. VELLUCCI2, M. MAMMUCARI3, G. FANELLI4

1Drug Addiction Department, ASL RMC, Rome, Italy 2Palliative Care and Pain Therapy Unit, University Hospital Careggi, Florence, Italy 3Primary Care, ASL RMC, Rome, Italy 4Department of Surgical Science, University of Parma, Parma, Italy; Pain Therapy Service, Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria Parma, University of Parma, Parma, Italy

Corresponding Author: Massimo Mammucari, MD; e-mail: massimo.mammucari@libero.it

physical, emotional and cognitive repercussions. Beyond the traditional duration-based defini- tions, CP has been recently defined as pain per- sistent beyond the time necessary for the healing of tissues, arbitrarily established from at least 3 months and/or supported by an identifiable pathology whose gravity is not sufficient to justi- fy the presence and or/pain intensity. However, according to the bio psychosocial model, CP should be considered an ongoing multifactorial process, influenced by physical, psychological and social factors1. Despite the detrimental im- pact of CP on patients’ quality of life, epidemio- logical data suggest that CP is often untreated or undertreated2.

Furthermore, CP is also the most common complaint for people seeking medical care, and pain under treated is one of the most common conditions reported by patients3.

Opioids have demonstrated their usefulness in the multimodal treatment aimed at a fast reintro- duction of the subject with CP in the social tex- ture, to enhance rehabilitation and improve sleep and overall quality of life4.

Physicians involved in the management of CP treat a lot of patients with opioids, whose effec- tive analgesic effect improves overall function- ing. Clinical experience and epidemiological re- search have demonstrated that opioids can safely and effectively relieve pain in a number of pa- tients with CP, while fears of addiction and ad- verse events could result in ineffective pain man- agement. However, considerable clinical experi- ence and a series of evidences suggest that in ap- propriately selected patients, opioids have low morbidity, low addiction potential and can pro- mote reduction in suffering, enhance functionali- ty and improve quality of life5.

2015; 19: 4898-4905

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Opioid risk addiction in the management of chronic pain in primary care

Recent epidemiological and clinical data demonstrate that only low percentages of patients treated with opioids for CP have a risk to devel- op addiction, with a prevalence rate similar to that observed in the general population6. Despite the iatrogenic risk can be considered as low, vali- dated tools for the early identification of patients at higher risk will help health professionals in the overall management of CP. Here we propose the Addiction Risk Questionnaire, a 28-item ques- tionnaire specifically conceived for general prac- titioners. However, in some specific EU coun- tries like Italy, general practitioners (GPs) are now considered as key actors in the long-term management of patients with CP.

Pathophysiology of Chronic Pain Chronic pain is associated with a broad spec-

trum of clinical conditions, including cancer, rheumatoid arthritis, fibromyalgia, osteoarthritis, low back pain (LBP), HIV/AIDS and spinal stenosis. The traditional broad classification dis- tinguishes between chronic cancer pain (CCP) and chronic non-cancer pain (CNCP). CCP can derive from different pathological conditions, in- cluding the invasion of tissues or bone by the cancer, nerve infiltration, obstruction of hollow organs, pain mediators and hormones secretion by the cancer itself. Table I summarizes different types of CP by nature (nociceptive, neuropathic, mixed)1.

Chronic pain is the result of the complex inter- action of nociceptive, neuropathic or mixed path- ogenic mechanisms. Nociceptive pain derives from the activation of primary afferent nocicep- tors in the peripheral nervous systems in re- sponse to mechanical, noxious or chemical stim- uli. The transmission to the central nervous sys-

tem (CNS) (brain stem, thalamus and cortex) via second order neurons of the dorsal horn of the spinal cord, allows the conscious recognition of a potential biological damage. A series of endoge- nous opiates and other neurotransmitters (i.e. serotonin, noradrenaline) are involved in the pain perception process, that is the result of the com- plex balance between stimulation and inhibition and is also dependent on emotional and behav- ioral factors1.

Neuropathic pain occurs when an injury to tissues sustains a primary lesion or dysfunction in the central nervous system. It can be mediated centrally or peripherally with differences in syn- dromes mainly depending on the types of fibers involved. It is usually described as burning or shooting/stabbing pain, while physical examina- tion can reveal numbness and/or coolness in the pain territory and sensitivity to a non-noxious stimulus. A further distinction should be made between stimulus-evoked and spontaneous (stim- ulus-independent) pain, likely sustained from dif- ferent underlying mechanisms. Chronic neuro- pathic pain is quite common in clinical practice and greatly impairs patients’ quality of life7.

Nociceptive and neuropathic components can coexist in CP8. In particular, untreated nocicep- tive pain can acquire a neuropathic component, thus sustaining a mixed pain syndrome9. The im- pact of CP with predominant neuropathic compo- nent has been underestimated for a long time due to the lack of specific epidemiological research- es. The prevalence of pain of predominantly neu- ropathic origin (POPNO) was 8% in a random sample of 6000 adults in UK, when specifically investigated10. Thus, this type of mixed pain ap- pears to be more common than previously sug- gested.

Primary nociceptive pain Primary neuropathic pain Mixed type pain

Osteoarthritis Postherpetic neuralgia Oncologic pain, with nerve infiltration Visceral pain Trigeminal neuralgia Complex regional pain syndrome I,

without nerve injury Headache Pain from HIV/AIDS Chronic back pain (nerve lesion or

dysfunction with nociceptive activation from ligaments, joints, muscles, tendons)

Ischaemic pain Complex regional pain syndrome II Oncologic pain without nerve damage Phantom pain Back pain without nerve damage Post-stroke pain, pain from multiple

sclerosis, spinal cord injury pain

Table I. Different types of chronic pain by nature1.

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Epidemiology of Chronic Pain Epidemiological and clinical data show that

chronic non-cancer patients are not a homoge- neous group and may present a wide range of bi- ological, psychological and social symptoms, of- ten complicated by depression, anxiety, somato- form disorders and substance abuse disorders11-14.

It is quite difficult to state an accurate estimate of CP prevalence in the general population due to disagreement on definition and to methodologi- cal issues. Recent data suggest that 10-55% of all adults have a form of CP. In the Pain Europe Study CP was defined as pain experienced for at least 6 months, reported in the last month and at least twice a week. The prevalence rate in 15 EU countries varied from 12% (Spain) to 30% (Nor- way), with variability likely due to differences in age stratification of studied populations, thera- peutic approaches, lifestyle and cultural ap- proach. Since CP is more common in the elderly, the proportion of subjects over 65 years in a spe- cific population will inevitably match a higher prevalence of CP in the respective country. As an example, in Italy and Spain, with two of the old- est populations at global level, the elderly sub- jects/children ratio is expected to reach four to one by the end of the first half of this century.

In the European Pain in Cancer study, up to 56% of 5084 patients with cancer reported mod- erate to severe chronic cancer pain at least monthly15. The same study revealed that treat- ment of cancer pain was often suboptimal and the assessment of its severity frequently poor.

Non cancer-pain is sustained from highly prevalent medical conditions, including os- teoarthritis, back pain, diabetic neuropathy and migraine headaches. Prevalence rates vary from 5% to 33% according to different source popula- tions. CNCP has an important economic impact, mainly due to patient discomfort, poor quality of life and increased use of health services16. In Eu- rope, osteoarthritis represents the most common cause of CP (42% of patients), followed by trau- ma or surgery (15%) and nerve damage or whiplash (4% each). Musculoskeletal pain, or non-specific pain, is another highly prevalent condition associated with CP. CNCP is common in primary care settings and often associated with distress and functional impairment1.

Diagnosis and Treatment of Chronic Pain The diagnosis of CP primarily requires the

identification of the nature of pain and the knowledge of underlying pathophysiology. Due

to the multifactorial nature of CP and the possi- ble overlapping of its components, a complex di- agnostic work-up is often required for an ade- quate clinical assessment. A general history and physical examination are necessary in all patients referring to physician for CP, while specific di- agnostic tests include radiography, computed to- mography (CT) or magnetic resonance imaging (MRI) scan1,17. In the “patient-centered” ap- proach, a clear picture of the multiple factors in- volved in the CP syndrome should be obtained at this stage. A complete evaluation include med- ical and pain history, previous treatment, age, sex, and social, cultural and psychological fac- tors. Assessment of pain should always be per- formed using validated tools to obtain successful pain management; nevertheless, well-designed surveys show the relative low tendency to the routinary use15,18. Compared to one-dimensional scales (i.e. visual analogue scales, verbal-rated scales and numerical-rated scales), multidimen- sional scales such as the Brief Pain Inventory, McGill Pain Questionnaire and the Western On- tario and McMaster University Osteoarthritis In- dex, are able to measure both pain intensity and the detrimental effects of pain on life activity and emotional functioning. Since pain is a purely subjective experience, pain intensity can be only compared intra-individually19.

Based on recent epidemiological evidence, the neuropathic component should always be investi- gated in CP. Nociceptive pain can acquire a neu- ropathic component if not treated promptly9. A diagnosis of POPNO is generally associated with worse prognosis, greater pain intensity and in- creased complexity of the treatment. In this view, it is highly recommended to screen CP patients for risk factors associated with the neuropathic component. The assessment should also include routine screening for psychosocial comorbidities, just as depression and substance abuse.

The goals of CP treatment should include im- proving of individual functionality and develop- ing self-management skills that focus on fitness and a healthy lifestyle. Opioids are considered the gold standard for the treatment of moderate to severe pain in CCP and, concomitantly, have been found effective for the treatment of moder- ate CNCP. Opioids have demonstrated their ef- fectiveness in a polimodal treatment of cancer pain, aimed at rapid reintegration of the subject in his own social context besides the overall im- provement of quality of life. Their effectiveness in the control of CCP has been reported in 70-

C. Leonardi, R. Vellucci, M. Mammucari, G. Fanelli

90% of patients. Concomitantly, their use has been associated with improvement in terms of morbidity and psychosocial distress. A series of issues, epidemiological and clinical evidences suggest that, in appropriately selected patients, opioids-based treatment for CP is characterized by a relative low addition potential and can sig- nificantly enhance functional activity level of pa- tients, finally improving their quality of life5.

The WHO analgesic ladder proposes to start the treatment of pain with non-opioid medica- tion; if pain is not adequately controlled, physi- cians should then introduce a weak opioid (step II). If also weak opioids are insufficient to treat pain, a strong opioid should be selected (step III). Several proposals for modification have ad- dressed the diagram of the analgesic ladder, but despite controversies, its educational value and a series of benefits deriving from its worldwide diffusion are uncontested20. While some authors focus on the need to enlarge the diagram with the IV step (including nerve block, PCA pump, neu- rolytic block therapy, spinal stimulators and epidural injection) several others proposed the abolition of the second step, thus starting with low dose of strong opioids earlier. This approach is supported by different clinical studies, which show that the efficacy of the second step is limit- ed over time (30-40 days) and the migration to strong opioids is primarily due to insufficient analgesia rather than adverse events. According- ly, the WHO has recently revised the Principles for the pharmacological management of pain in children with medical illnesses. In particular, the former three-step ladder has been abandoned in favor of a two-step approach, excluding the use of intermediate potency opioids (previous second step). However, according to the WHO Guide- lines Development group, the benefits of using an effective strong opioid outweigh the benefits of intermediate potency opioids, and although recognized, the risks associated with strong opi- oids are acceptable when compared with the un- certainty associated with the response to codeine and tramadol in children21.

Addiction, Tolerance and Pseudoaddiction Addiction is defined as a chronic, relapsing

brain disease, characterized by compulsive drug seeking and use despite harmful consequences. The development of drug addiction can be con- sidered the result of a complex interaction be- tween biological and environmental factors. The drug intake is the final step of compulsive dy-

namics with low or no ability of the subject to control over it. The strong and overwhelming wish to obtain the drug (craving) can’t be over- come if people, places or objects previously as- sociated with addiction development are present. The “brain-reward” model explains the behav- ioral patterns as drug intake produces rewarding effects due the euphoric perception following the assumption, and reinforcing effects which are re- dundant due to the supporting (reinforcing) effect on a series of associated behaviors.

While the concept of addiction may include the symptoms of physical dependence and toler- ance, physical dependence and/or tolerance alone does not equate with addiction22. Tolerance should only be considered an adaptive conse- quence of drug exposure, so that increasing doses are necessary to obtain adequate pain control22.

In the last decades a series of concerns about the safety, efficacy and appropriateness of opi- oids in the treatment of chronic patients (CPPs) have been reported. The main point of weakness of opioids as a drug-class was identified in their long-term safety profile, tolerance, interferences with physical and/or psychosocial functioning and addiction. The risk to develop addiction should be reasonably considered in opioids naïve patients without a previous history of addiction. Nevertheless, available data are quite reassuring, suggesting that the incidence rate is similar to that observed in the general population23-29.

The Boston Collaborative Surveillance Pro- gram involved 11.882 subjects treated with opi- oids for a wide range of indications. Excluding those subjects with a positive history of sub- stance abuse, only four cases of addiction were reported30. Similarly, a national survey involving over 10.000 patients in long-term treatment with opioids did not find any case of addiction. These data support the assumption that the fear to in- duce addiction is completely unfounded, despite being one of the most common barrier for opi- oids prescription28.

Severe CCP can hide pain of different nature and of lower intensity that can overcome when treatment with opioids reduces CCP intensity. A possible mistake is to consider the consequent request of more effective drugs an addictive be- havior.

With the term “Pseudoaddiction” some au- thors describe a reversible condition observed in patients with undertreated CP, characterized by erratic behavior and resolved when pain control is achieved. The patient focuses on obtaining

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Opioid risk addiction in the management of chronic pain in primary care

4902

medications and thus induces the physician to suspect an addictive behavior. Pseudoaddiction is generally consequent to low, ineffective dosages of opioids and does not represent a risk factor for the development of addiction. Nevertheless, if undertreatment is incorrectly prolonged, the risk of addiction increases as the subject may start to take opioids by himself in the attempt to gain an effective dose for pain control31.

Many physicians remain reluctant to prescribe opioids for CP, mainly because of the fear of ia- trogenic addiction, a frequently reported situation in clinical practice. Opioids are theoretically able to activate the reward system in the CNS of all in- dividuals. These central effects can be interpreted and experienced in different manners among sub- jects: in some cases they are elaborated as not im- portant and do not induce any variation of the in- dividual psychological and behavioral pattern. In other cases, these effects can represent the basis for the onset of drug misuse and of a progressive instauration of addiction. Despite all opioids are able to induce iatrogenic additive behavior due to their pharmacodinamic properties, this should not be considered as a pathological condition by it- self, but a physiological and reactive process as- sociated to tolerance development. Thus, the presence of addiction during opioid-based therapy should not be intended as a medical illness nei- ther its anticipation. Similarly, pseudoaddiction should not be considered as predictive of addic- tion, except in the case it is wrongly maintained over time. However, recent experimental studies in neurobiology show how in neuropathic pain models, prolonged treatment with opioids is not associated with increased dopamine release in the CNS and, thus, unable to activate the reward cir- cuitry32. A series of genetic, psychosocial and drug-related factors able to influence the percep- tion of additive effects of opioids should, there- fore, be identified and considered for evaluation of iatrogenic risk.

GPs’, Chronic Pain and Opioid Addiction Risk

The management of CP involves a number of difficulties. These include the onset of treatment, its monitoring over time, the customization based on individual needs, the treatment of severe pain in the frail elderly, the switch from a drug to an- other on the basis of efficacy and safety and the evaluation of risk of drug addiction.

The role of GPs in the management of patients with moderate to severe CP is crucially based on

their ability to recognize the different levels of intervention for each selected patient/case. The GP can early select those cases requiring the acti- vation of the specialists’ network from those that can be managed in primary care. Recent data show how GPs’ intervention can lead up to a sig- nificant reduction of pain level, especially when informatics technologies are adequate to share a common and always updated strategy with spe- cialists. Furthermore, a close information ex- change and a shared report form have been found to produce macroeconomic benefits.

The key role of the GP in the management of patients with CP has been recently stated in the Italian law (law n. 38, May 2010) regarding pain treatment and palliative care. It defines a new ex- ample of “home-based” management of CP. However, due to the great amount of information about social, psychological and familiar status of patients, GPs can easily detect cases requiring further or critical attention in terms of prevention and treatment. Beyond the ability of GPs to se- lect patients requiring different levels of inter- vention, their capability to monitor patients over time is another key factor supporting the strength of the new Italian normative asset. GPs are able to detect a series of conditions occurring during the treatment period, including drug-drug inter- actions, tolerance, addiction and safety concerns. These evaluations can be easily shared with spe- cialists before dose adjustments and/or other in- terventions. In the view of iatrogenic risk, de- spite the very low frequency of drug addiction observed among patients treated with opioids, a validated tool able to identify subjects with high- er levels of vulnerability will be useful for GPs, especially in countries as Italy where new nor- mative provide for their central role in the man- agement of CP33.

The GP has the opportunity to establish a last- ing partnership with the patient34. With this part- nership, the GP provides counseling, continuity of care, and prevention of forms against misuse of drugs. The doctor-patient partnership has a pivotal role in prevention management and pa- tient care.

GPs are early able to identify different “types” of patients. In fact, GP has knowledge of his pa- tient, his attitudes, personal and family, the de- gree of intensity of pain and disease that gener- ates it, the co-existing medical conditions and re- lated therapies, can identify the person with per- sonality at risk. In the case of a patient with per- sonality at risk, but who may need treatment with

C. Leonardi, R. Vellucci, M. Mammucari, G. Fanelli

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Opioid risk addiction in the management of chronic pain in primary care

opioid analgesic, it is appropriate to administer the lowest effective dose, preferably at normal release frequent monitoring of the clinical re- sponse (Table II). The involvement of GPs in the course of treatment of the patient with pain, as suggested by a recent expert opinion35, allows you to monitor and prevent cases against misuse and to avoid under treatment of patients with un- necessary pain.

Questionnaire for the Detection of Opioid Addiction Vulnerability

Despite recent data have demonstrated the low potential of opioids to induce addiction when used for the treatment of CP, several psychologi-

cal and social factors can affect the interplay of subjects with the rewarding effects of the drug, thus increasing their vulnerability to opioid ad- diction. GPs should be able to select those cases requiring strategies or interventions to minimize the risk of drug abuse/misuse. Some authors fo- cused on the need of specific validated tools to evaluate iatrogenic risk, mainly depending from the high rate of drug misuse observed in last decades in countries like US34. Notably, in coun- tries with more strict prescribing procedures (i.e. Italy) the iatrogenic risk has quite always been lower. Several tools have been made available in order to identify potential opioids abusers in the context of CP management (Screener and Opioid

N. Questionnaire Yes No

1 I’m / I smoked in my life for more than six months continuously 2 I take an alcoholic drink every day before meals or a digestive after meals 3 I use / I have used drugs to treat anxiety and depression 4 My parents, brothers or sisters have had the need to take drugs for the treatment of anxiety and depression 5 I use / have used drugs in my life for more than six months continuously 6 In my family there were problems with drugs or alcohol

Neither Totally Quite agree nor Quite Strongly agree agree disagree disagree disagree

7 I spend more time than I should every day in front of the PC, smartphone or console not for work

8 I always run the risk of taking penalties / fines in my life 9 Because of my behavior I changed school several times

10 I often try the luck 11 The drugs can not help me heal my pain 12 I’ve always been considered a troubled student by teachers 13 I can always control my anger 14 Everybody hates me 15 I often like to look for exciting experiences 16 I always want to exceed the limit 17 When I wake up, I immediately desire to smoke 18 I have been criticized for the way I drink 19 I have a satisfying sex life 20 After all sexual relations, although satisfactory, I feel the

need to have others in a short time 21 I have a lot of trust into myself 22 During this time I have problems at work 23 During this time I have problems in the family 24 I sleep soundly 25 I feel depressed 26 I feel I have the resources to deal with the difficulties of life 27 When I feel the desire for something, I do everything

to achieve it 28 I follow closely the requirements of the doctor

Table II. The validation process includes a score for each question and an overall score to identify patients at risk. This ques- tionnaire, until its validation, shows a list of information that the doctor can obtain from the medical history of the patient.

Addiction risk questionnaire. Rapid Indicators of Suspected Vulnerability to Addiction in patients with chronic pain (RISVA), by Claudio Leonardi, MD.

treated with opioids for CP have a risk to devel- op addiction, with an incidence rate similar to that observed in the general population.

The combined intervention between the spe- cialist and the general practitioner (a successful model recently introduced in the Italian law), the application of tools for prevention, the active monitoring, the conscious participation of the pa- tient, and the case-oriented management are the key factors for an adequate CP management and iatrogenic risk reduction.

–––––––––––––––––––– Acknowledgements Thank to Ennio Sarli (Progetti Live Surgery srl, Florence), Francesco di Fant (Pain Interregional Network, Rome) Diego Tosi (Studio Associato Tosi & Latella, Rome). Edito- rial assistance for the preparation of this manuscript was provided by Laura Brogelli, PhD.

–––––––––––––––––-–––– Conflict of Interest The Authors declare that there are no conflicts of interest.

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Conclusions

Effective CP treatment is a clinical and ethical imperative. Opioids have been found effective in the polimodal treatment of cancer pain, aimed at rapid reintegration of patients in their own social texture, and thus improving their overall quality of life. Recent epidemiological and clinical data demonstrate that only low percentages of patients

Appropriate use of opioids to manage pain in patient at risk

Multimodal therapies (aiming at opioid-sparing) Opioid titration Long-acting formulations only for persistent pain Prefer abuse-deterrent formulation and child-proof

packaging Frequent assessment of patient Prefer centralized prescription of opioids Periodic monitoring of drug consumption Continuous counseling Screening patients at potential risk Sharing of patient at risk with other specialists

Table III. Strategies to manage the opioid treatment, modi- fied from35.

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