DOI: 10.12809/hkmj164920
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
Opioid therapy for chronic non-cancer pain: guidelines for Hong Kong
CW Cheung, MD, FHKAM (Anaesthesiology)1; Timmy CW Chan, FFPM ANZCA, FHKAM (Anaesthesiology)2; PP Chen, FFPM ANZCA, FHKAM (Anaesthesiology)3; MC Chu, FFPM ANZCA, FHKAM (Anaesthesiology)4; William CM Chui, MSc, BPharm (Hon)5; PT Ho, FRCPsych, FHKAM (Psychiatry)6; Flori Lam, BHSc(RN)7; SW Law, FRCSEd(Orth), FHKCOS8; Josephine LY Lee, MSc9; Steven HS Wong, MB, BS, FHKAM (Anaesthesiology)7; Vincent KC Wong, BCPS, MPharm5
1 Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, The University of Hong Kong, Pokfulam, Hong Kong
2 Department of Anaesthesiology, Queen Mary Hospital, Pokfulam, Hong Kong
3 Department of Anaesthesiology and Operating Services, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong
4 Department of Anaesthesia, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
5 Department of Pharmacy, Queen Mary Hospital, Pokfulam, Hong Kong
6 Consultation and Liaison Psychiatry Team, Kwai Chung Hospital, Kwai Chung, Hong Kong
7 Department of Anaesthesiology and Operating Theatre Services, Queen Elizabeth Hospital, Jordan, Hong Kong
8 Department of Orthopaedics and Traumatology, Prince of Wales Hospital, Shatin, Hong Kong
9 Occupational Therapy Department, Prince of Wales Hospital, Shatin, Hong Kong
Corresponding author: Dr CW Cheung (
 Full paper in PDF
Opioids are increasingly used to control chronic non-cancer pain globally. International opioid guidelines have been issued in many different countries but a similar document is not generally available in Hong Kong. Chronic opioid therapy has a role in multidisciplinary management of chronic non-cancer pain despite insufficient evidence for its effectiveness and safety for long-term use. This document reviews the current literature to inform Hong Kong practitioners about the rational use of chronic opioid therapy in chronic non-cancer pain. It also aims to provide useful recommendations for the appropriate, effective, and safe use of such therapy in the management of chronic non-cancer pain in adults. Physicians should conduct a comprehensive biopsychosocial evaluation of patients prior to the commencement of opioid therapy. When opioid use is deemed appropriate, the patient should provide informed consent within an agreement that specifies treatment goals and expectations. A trial of opioid can be commenced and, provided there is progress towards treatment goals, then chronic therapy can be considered at a dose that minimises harm. Monitoring of effectiveness, safety, and drug misuse should be continued. Treatment should be stopped when opioids become ineffective, intolerable, or misused. The driving principles for opioid prescription in chronic pain management should be: start with a low dose, titrate slowly, and maintain within the shortest possible time.
Chronic pain is pain that persists beyond the usual time of healing, usually marked as 6 months or even 3 months by the International Association for the Study of Pain (IASP).1 Chronic pain arises from complex changes to central or peripheral nervous system signalling, or both. The perception of pain is modulated by an individual cognitive factors and the environment,2 and can significantly compromise daily function, resulting in an important health issue. Hong Kong survey data estimated the prevalence of chronic pain to affect 10.8% of the population in 2000 and 35% in 2007.3 4 Survey participants with chronic pain from an earlier study reported a significant impact on their daily lives.3 Moreover, chronic pain placed a substantial load on productivity, with an estimated loss of approximately 0.2 working days per person in the working population per year, and on health care resources, with almost three quarters of respondents consulting a health care practitioner. The latter survey found that reports of chronic pain were strongly associated with co-morbid mental health problems and anxiety.4
Opioid therapy is accepted for acute pain and cancer pain,5 6 but its effectiveness and safety for chronic non-cancer pain (CNCP) remains contentious. By definition, CNCP refers to non-malignant pain that lasts beyond the time of tissue healing, or longer than 3 months.1 Authors cite weak evidence for opioid use for CNCP due to the lack of randomised controlled trials with long follow-up.7 8 Based on systematic reviews, opioids for CNCP—including neuropathic pain, nociceptive pain, and arthritic pain—confer some benefit by reducing pain intensity and improving functional outcome compared with placebo and other non-steroidal anti-inflammatory drugs,9 10 11 12 13 but high-quality studies are rare, and treatment duration is short, ranging from 2 weeks to 6 months. A proportion of patients in the studies reviewed did not progress to long-term therapy due to adverse effects.12 Discontinuation rates from adverse effects were almost 30%, with the most frequently reported events being constipation, nausea, dizziness, drowsiness, and headache.12
The potential to develop opioid abuse or addiction with long-term therapy is also a concern. In studies reviewed, addiction or abuse rates were reported to range from 0.27% to 0.43%.12 14 15 Deaths related to opioid analgesic overdose have been increasing, and is being linked to an increase in opioid prescriptions for pain.16 17 Indeed, chronic opioid exposure from prescription appears to be a strong risk factor for an opioid misuse event in patients just diagnosed with CNCP.18 Other potential harm from chronic opioid use includes increased fracture risk,19 androgen deficiency,20 respiratory depression,21 cognitive impairment,22 impaired immunity,23 and opioid-induced hyperalgesia.24 25
Global consumption of opioids for moderate-to-severe pain increased approximately 15-fold from 1980 to 2012.26 Generally, opioid consumption of countries in Asia, including Hong Kong, is low relative to the global picture (Fig27), but showing an increasing trend.27 28 Physicians in Hong Kong may be reluctant to prescribe opioids for long-term therapy due to fear of patient addiction. There may also be a cultural prejudice against opioid use stemming from a history of China’s involvement in the global opium trade in the early part of the century.29 Other possible barriers to prescription and patient care may include inadequate physician education about pain management, and lack of physician-patient communication about the seriousness of the pain problem. The absence of a central registry for opioid prescriptions, and the limited number of addiction specialists are potential local logistical barriers. With the introduction of opioid choices in Hong Kong, however, the prescription of strong opioids for long-term treatment may become more common. Examples of strong opioids for CNCP used in Hong Kong are listed in Box 1.30

Figure. Global morphine equivalence consumption (2013)27
The consumption statistics are displayed in milligrams per capita, which is calculated by dividing the total amount of opioid consumed in kilograms by the population of the country for that particular year (cite United Nations population data). This provides a population-based statistic that allows for comparisons between countries
Reproduced with permission from Pain & Policy Studies Group. Opioid consumption maps—Morphine equivalence (ME), mg/capita, 2013

Box 1. Strong opioids registered in Hong Kong for chronic pain management30
Guidelines governing the use of opioids for patients with CNCP have been issued in different countries according to their needs.31 32 33 34 35 36 37 38 The Hospital Authority has recently introduced an opioid guideline for CNCP for public hospital use. A similar guide is not readily available for physicians who are involved in CNCP management but practise outside Hospital Authority in Hong Kong. This document aims to serve as a resource and uniform guide for the appropriate, effective, and safe use of chronic opioid therapy (COT) in the management of CNCP in adults based on local considerations; COT is regarded as the use of strong opioids for more than 3 months.39 This guideline provides recommendations about patient selection, risk screening, initiation of COT, and monitoring during COT, based on a review of the current literature. The target audience is all physicians, especially non-pain specialists, and other health care professionals involved in the multidisciplinary management of the patient with CNCP, who are considering prescribing COT.
General considerations for using opioid in patients with chronic non-cancer pain
The biopsychosocial model describes pain as bodily disruption shaped by an individual’s subjective perception. Biological processes, emotions, and social factors all influence the pain experience.2 Consequently, chronic pain is a complex condition that requires a multidisciplinary approach to both evaluation and management, preferably in a coordinated treatment programme.40 41 The IASP recognises the effectiveness of multidisciplinary pain programmes for chronic pain, and recommended the establishment of multidisciplinary pain clinics or pain centres; the latter of which should be associated with a research or academic programme.40 Staff at both pain centres and clinics should include practitioners from various disciplines deemed expert in pain management. Physicians, nurses, mental health professionals, and physical therapists are among those who comprise a team that coordinates diagnosis and management, with constant communication, preferably in one setting.40 41 Essential elements of multidisciplinary pain programmes address pain management, psychosocial recovery, and physical rehabilitation, and include medication, physical therapy, and cognitive and behavioural strategies.42 Such programmes have been proven clinically effective and cost-effective.43 44 45
In fact, COT is just part of the multimodal strategy to manage CNCP. Experts do not recommend opioids for first-line treatment of CNCP.34 36 38 Non-opioid treatment options, both non-pharmacological and pharmacological (eg typical analgesics), should be tried first. Despite limited evidence to support the safe and effective use of opioids in CNCP, they may be considered for selected patients who have moderate-to-severe pain and who have not responded adequately to non-opioid therapy.38 In accordance with the biopsychosocial model, treatment of CNCP should address the physical, psychological, and social aspects of the pain problem.41 Treatment of CNCP should thus aim to reduce pain and support patients’ physical, psychological, social, and work functioning.40 The goals of COT include pain reduction, reduction of pain-associated symptoms such as anxiety and sleep problems, and improvement of daily function.46 47 These goals should be individualised and utilise achievable milestones without excessive use of opioids.46 Indeed, daily function outcomes were deemed important by survey participants with chronic pain,48 and should be targets for improvement along with pain control (Box 2).

Box 2. Goals of chronic opioid therapy
  • Chronic opioid therapy should be considered only as part of a multidisciplinary pain management strategy.
  • Opioids should be prescribed only after exhausting other pharmacological and non-pharmacological treatment options.
  • Treatment goals acceptable to both patients and their physicians should be set when COT is considered.
  • When prescribed, COT should aim to reasonably reduce pain and its associated symptoms, as well as improve functional outcomes.
Patient evaluation and selection
Prior to starting COT, a comprehensive patient evaluation should be carried out to form a diagnosis, establish the cause of pain, describe pain intensity, and determine a patient’s risk profile with the use of opioids.38 46 The evaluation informs on the suitability of a patient for COT, and, if the decision to pursue COT is made, provides the foundation for individualising a treatment plan. A thorough history and physical examination with appropriate investigations are essential. The pain complaint should be thoroughly investigated with regard to characteristics, underlying factors, and effects on the patient’s functional status.38 46 Assessment should include a medical and psychosocial history, including previous medication, general health, family support, and work status. For example, increased use of opioids for pain control prior to spine surgery was found to be associated with worse postoperative outcomes, such as increased demand for opioids after surgery, and decreased incidence of opioid independence 1 year after surgery.49 50 This highlights the need for a complete evaluation and screening of each patient prior to opioid use. Evaluation findings may impact subsequent patient counselling and treatment planning.
The rate of problematic opioid use or aberrant drug–related behaviour in patients with CNCP on COT is 11.5%.51 Prevalence of substance use disorder among patients with CNCP, with or without opioid use, ranges from 3% to 48%.52 Because problematic opioid use complicates pain treatment and may cause significant harm, a patient’s risk for opioid abuse, misuse, or addiction must be assessed prior to COT.38 46 53 54 Screening helps the physician to anticipate the patient’s risk of developing aberrant behaviour while on COT.53 54 Family and personal history of substance abuse, a history of psychiatric or mood disorders, and younger age have not been validated as predictive of opioid misuse, but have been shown to potentially increase risk.52 55 56
The physician can utilise structured clinical interviews and self-reports to elicit these factors.52 56 Questionnaires such as the Opioid Risk Tool, which assigns weights to predictive factors of opioid misuse, may be useful.57 The presence of apparent predictors of misuse such as a personal or family history of substance abuse or addiction does not necessarily preclude the use of opioids, but may affect structure of therapy (eg closer monitoring, stricter prescription practice) and require additional consultation from specialists, including psychiatrists.54 Urine drug screening (UDS) may be a useful aid in detection of latent drug abuse. Every assessment must be thoroughly documented.
According to addiction specialists from the Hong Kong College of Psychiatrists, screening by psychiatrists for suitability of high-risk patients for COT may not be useful, as evidence to support reduced substance abuse risk through conjoint selection by pain specialists and psychiatrists is lacking. There is also inadequate evidence that the future risk of opioid abuse is reduced by treating substance abuse prior to COT; thus, the decision to make this treatment a prerequisite for COT rests on the pain management team (written communication, Clinical Division of Substance Abuse & Addiction Psychiatry, Hong Kong College of Psychiatrists, 2016). Patients with active substance abuse (opioid, non-opioid, or both) and psychological disturbances may be referred to substance abuse clinics (SACs) in Hong Kong for pre-COT psychiatric treatment (Appendix 1).

Appendix 1. Referral channels and clinics for patients with opioid misuse, and patients who will need discontinuation of opioid treatment, suggested by the Hong Kong College of Psychiatrists
(written communication, Clinical Division of Substance Abuse & Addiction Psychiatry, Hong Kong College of Psychiatrists, 2016)
  • Patients considered for COT should have a thorough physical, psychological, and social assessment.
  • Risk of substance misuse or addiction should also be assessed for appropriate treatment planning.
Prescription of chronic opioids
Informed consent and documentation
Guides on COT for CNCP recognise the need for informed consent to explain the benefits, risks, and complications of COT before a trial of opioid therapy, and when the decision to use COT is reached.38 46 Consent in the form of a written plan or treatment agreement, or opioid contract, can set expectations between the physician and patient regarding their actions and treatment targets.13 38 46 The usefulness of a contract in promoting adherence to a COT regimen lacks evidence, however. Also, use of a contract has underlying ethical issues relating to patient autonomy and the assumption of potential opioid abuse.13 58 Nevertheless, if utilised, an agreement should outline information on COT and alternative treatment options, benefits, risks (which include adverse effects, behavioural risks, and medical complications), steps to reach treatment goals, means of monitoring improvements, and conditions for continuing or discontinuing therapy (Appendix 2).13 38 58 Specifically, it may include from whom and where the patients should obtain their prescription, the number and time of office follow-ups, and expectations on use of UDS.46 58 The agreement should be reviewed continually during treatment.46

Appendix 2. Sample elements of an opioid informed consent and agreement13 38 58
Trial of opioid therapy
An opioid trial assesses patients’ responsiveness to opioids. Dose titration during an opioid trial determines the lowest effective dose with the least or minimal side-effects for an individually tailored programme.59 The choice of opioid should be based on factors related to the individual patient, such as previous response to opioids, health status, treatment goals, predicted risks; on medication-related factors, such as availability and pharmacological and adverse effect profiles; and on physician experience and expertise.33 36 59 Parenteral forms of opioids are not recommended for an opioid trial due to risk of abuse.33 36
Opioids should be titrated slowly, for example, at increments of 10 to 50 mg equivalent per day of a long-acting opioid, until the optimal dose that provides benefit with the least side-effects is attained.33 47 60 The optimal dose is suggested to lead to a 30% pain reduction (based on an 11-point scale) that does not cause significant adverse effects.33 61 A trial of therapy may last weeks or months. Duration can be set from 4 to 6 weeks, or up to 90 days in some pain centres.46 47 60 The target results and duration of the trial period should be understood and agreed by the patient.46 60
Prescription for special concerns
Driving and work safety are potential concerns when COT is used. Studies have not shown impairment of driving-related activities with opioids,13 62 63 but patients should be informed of factors related to opioid use that may cause impairment, including initiating opioids or changing opioid dose, poor sleep, severe pain, and concomitant intake of alcohol or sedating medications.13 33 38 Patients should be advised to avoid driving or participating in potentially dangerous activities if they show signs of impaired cognition or psychomotor ability, such as somnolence, poor coordination, or decreased concentration.33 38
Pregnant patients or patients planning to get pregnant should be counselled on the risks of COT during pregnancy. Such therapy during pregnancy has been found to be associated with neonatal withdrawal syndrome, poor birth outcome, and certain birth defects.64 65 66 Because of this, COT during pregnancy is not encouraged unless the potential benefits outweigh the risks.38 47
  • Informed consent should be obtained before an opioid trial as well as before the start of COT.
  • Prior to COT, an opioid trial should be conducted to assess patient response and to determine an optimal opioid dose.
  • The choice of drugs and initial dosing should be individualised according to the drug profile, patient characteristics and goals, and physician experience.
  • Patients on opioids who show signs of impaired cognition or psychomotor activity should be cautioned against driving and other potentially dangerous activities.
  • Use of COT during pregnancy is discouraged because opioids may lead to poor birth outcomes.
Monitoring during chronic opioid therapy
Ongoing assessment and regular monitoring during COT allows physicians to characterise patients who continue to benefit from opioids or who may need changes in their treatment programme. During an opioid trial, the patient is regularly monitored, usually at weekly intervals, to assess the four A’s: analgesia, activity, adverse effects, and aberrant behaviour.33 60 67 The dose is adjusted based on changes in pain intensity, improvements in daily function, and development of side-effects and of aberrant behaviour.33 35 46 Validated pain assessment tools such as the Brief Pain Inventory or the Pain, Enjoyment, and General Activity scale may be used at baseline and at regular intervals thereafter to describe changes in pain relief and function.33 46 47 Drug-related behaviour can be monitored through patient interviews, observation, and UDS.
Evidence is lacking on the reliability of UDS in predicting aberrant behaviour, and UDS still needs to be evaluated if it improves clinical outcomes.37 Nonetheless, UDS provides important information on adherence to the treatment plan and existence of possible drug misuse when appropriately used with other monitoring tools. Although other biological specimens may be tested, obtaining urine is considered practical and convenient, and results can be obtained within a few days to allow modification of patient care.68 Physicians should be aware of limitations in interpreting results and should maintain communication with testing laboratories to resolve any doubts.68 In addition, differential diagnoses for each result should be considered, for example, absence of prescribed drug in the urine could indicate non-access to required prescription, or diversion of the prescription.37 69 These considerations should facilitate a discussion with the patient in order to improve care. Prior to the onset of opioid therapy, it is important to educate the patient and specify the objectives of UDS in the treatment agreement to avoid confrontation and uphold a strong physician-patient relationship.69
There is no agreement on the frequency of UDS, but it should be performed as frequently as necessary according to the patient’s risk for misuse, occurrence of aberrant behaviour, and on availability of the test.37 47 If aberrant drug behaviour is noticed, the patient may need more intensive monitoring and referral to a pain or substance abuse specialist.47 60 Continuation of opioid therapy may be agreed upon by physician and patient if there is note of progress towards the patient’s goals as determined from regular monitoring.60 If the patient is deemed suitable to continue opioids in the long term after an opioid trial has established a stable dose, monitoring of the four A’s is undertaken at regular intervals.60 Intervals can be as far apart as 6 months for patients with no risk issues, or as frequent as monthly for those at risk of opioid misuse, or those taking doses near the threshold level.47
  • Monitoring during COT should include documentation of pain intensity, level of functioning, presence of adverse events, and adherence to prescribed therapies.
  • Validated pain assessment tools may be used at baseline and regularly thereafter to describe changes in pain and function.
Opioid rotation
Patients who initially responded but have become tolerant despite escalating doses, and those in whom side-effects limit dose increases, may consider an opioid switch or rotation.70 Despite the lack of evidence from controlled studies for the clinical effectiveness of opioid rotation,71 72 the strategy may be useful based on observed differences in individual responses to various opioids.73 This occurrence may be explained by genetic variations in receptor subtypes that modulate drug effects, and that also potentially promote incomplete cross-tolerance among opioids.74
Opioid rotation involves selection of a new opioid, determination of its appropriate initial dose, and subsequent titration for a satisfactory balance of efficacy and side-effects.70 Use of an equianalgesic table can facilitate estimation of the new drug’s initial dose.33 75 76 77 78 Its dose should approximate the dose of the previous drug (Table 133 75 76 77 78). Drug potencies reflected by the reference table may be underestimated74; therefore, experts support an initial automatic reduction in the estimated equianalgesic dose of the new drug by 25% to 50% for safety.70 If the previous dose was high, a reduction by at least 50% is recommended by some authors.33 Exceptions to this include a switch to methadone, which should use a reduction of 75% to 90%, and switch to transdermal fentanyl, which does not require a reduction.70 This initial computation should be adjusted or retained based on the patient’s clinical situation. Subsequent drug titration should be based on this initial dose.70

Table 1. Conversion factors for equianalgesic dose of selected opioids33 75 76 77 78
  • When switching to a new opioid, calculate the equianalgesic dose using a reference equianalgesic table.
  • Reduction of the calculated dose is recommended for safety.
  • Prior to a new opioid trial, adjust the dose further after reassessment of the patient’s clinical situation.
Management of side-effects and problematic opioid use
Constipation, nausea, headache, and sedation are the most frequently reported opioid side-effects in clinical trials.12 Many side-effects reportedly diminish over time,12 but some side-effects such as constipation and vomiting may be severe enough to prompt discontinuation from trials. Constipation, in particular, may not diminish and cause significant severe discomfort.79 Opioid dose adjustment, opioid rotation, and proactive therapy (eg stool softeners for constipation) are strategies that can minimise severity of adverse effects.21 79 Common opioid-associated side-effects should be anticipated and managed appropriately when identified to maintain compliance (Table 2).33

Table 2. Opioid-associated side-effects and complications33
Problematic drug use or aberrant drug behaviour may arise from opioid use. As described previously, patients on COT who are at high risk of opioid misuse or addiction may need additional consultation with addiction experts, and a restructuring of their programme to include frequent, close monitoring.33 46 47 54 In addition to patient interviews, proper drug use may be monitored through methods such as regular visits, pill counts, and UDS.80 Physicians should attempt to identify the cause of behaviour that suggests the possibility of opioid misuse. It is important to be aware of pseudo-addiction, which apparently exhibits the same compulsive behaviours for opioids as in addiction, but is due to inadequate pain relief from undermedication.81
When drug misuse is identified, the patient should undergo a complete re-evaluation for treatment modification.33 Repeated, serious aberrant behaviour requires discontinuation of COT and referral to substance abuse specialists for detoxification.33 47 Referral channels and treatment through SACs for patients with significant psychological disturbance or addiction features (eg aberrant drug behaviour, other substance abuse such as benzodiazepines) are available in Hong Kong (Appendix 1).
  • Anticipate common side-effects and manage appropriately.
  • If problematic drug use is recognised, re-evaluate the patient and modify treatment.
  • Discontinue COT if aberrant behaviour is present. Referral to substance abuse specialists is warranted.
Upper dose limit and exit strategy
The goals of COT should be revisited at regular intervals to see if patients can meet their targets within a defined dose range, determined from the initial daily dose titrated to the lowest effective dose. It is recommended that the upper dose titration limit should not exceed 120 mg of oral morphine or its equivalent, or 200 mg in some centres.33 38 47 60 If the daily dose exceeds this limit, a reassessment of the pain condition, potential for misuse, and need for more frequent monitoring is warranted.33 38 Indications for discontinuation include no change or improvement in therapeutic goals despite escalating doses, intolerance to side-effects, and persistence of aberrant behaviour. If the decision to discontinue opioids is reached, the opioid should be tapered to avoid withdrawal problems.33 46 47 60
The tapering plan is variable, but generally, a reduction of 10% per week from the original dose is well tolerated.33 47 60 A faster or slower rate may be suitable depending on the patient’s situation. Physicians should monitor patients for changes in pain and for the appearance of side-effects, withdrawal symptoms, and behavioural issues. These concerns should be properly managed. In some cases, a referral to the appropriate specialists may be warranted. Likewise, patients who fail to benefit from COT and who need discontinuation may be referred to SACs in Hong Kong for detoxification and rehabilitation services (written communication, Clinical Division of Substance Abuse & Addiction Psychiatry, Hong Kong College of Psychiatrists, 2016).
  • Chronic opioid therapy should be stopped if patients experience no progress towards treatment goals, experience intolerable side-effects, or are engaged in repeated aberrant drug-related behaviours.
  • Opioids should be tapered to avoid withdrawal.
Strong opioids play a role in the multimodal management of CNCP. They may be appropriate for selected patients despite insufficient evidence of effectiveness. Opioid therapy is potentially associated with common side-effects and significant harm; thus, careful patient selection by a thorough patient evaluation prior to treatment, and careful dose titration and monitoring during initiation and long-term therapy, are all recommended steps for rational opioid use in CNCP. Whenever opioid is prescribed for chronic pain management, it should be started with a low dose and titrated slowly, as well as maintained for the shortest possible time.
We would like to thank the Clinical Division of Substance Abuse & Addiction Psychiatry, Hong Kong College of Psychiatrists for their advice and opinions.
All authors are members of the working group for Guideline for Chronic Opioid Therapy in Chronic Noncancer Pain, Hospital Authority Multidisciplinary Committee on Pain Medicine, Hospital Authority, Hong Kong. All authors have disclosed no conflicts of interest.
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